The DOI matches its Crossref record; 77 of the 77 references it cites were found in a registry or an index; none of the 50 sources its claims cite is checked for support yet.
Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation
Open accessAbstract
How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
Neuronal differentiation from human NPCs is marked by shutting off aerobic glycolysis and shifting to oxidative phosphorylation, with loss of HK2/LDHA, PKM2-to-PKM1 splicing, and decreased c-MYC/N-MYC. Constitutive HK2/LDHA expression kills differentiating neurons, while increased PGC-1α/ERRγ maintain rather than increase metabolic and mitochondrial gene expression.
Key findings
- Differentiation from NPCs to neurons involves loss of HK2 and LDHA protein, a PKM splice switch from PKM2 to PKM1, and a neuron-specific OGDH splice form lacking a Ca²⁺-binding motif; c-MYC and N-MYC protein levels fall by ~70% and ~85%, respectively.
- Neurons show lower glycolytic/TCA metabolite levels and higher oxidative capacity: basal and maximum OCR rise from ~82 and 130 pmoles/min/10 µg in NPCs to ~98 and 183 in 3-week neurons, while lactate/glucose ratio falls from ~1.61 to ~0.35.
- Constitutive HK2 and LDHA expression during differentiation causes neuronal death: ~40% condensed nuclei versus ~6% in controls, with ~40% GFAP-positive glial cells versus ~4% in controls; extra pyruvate (5 mM) rescues neuronal death but not glial increase.
- PGC-1α and ERRγ increase ~3–4 fold and ~2.8–3.4 fold, respectively, and are required to maintain expression of glycolysis, TCA, and mitochondrial respiratory complex genes, even though most mitochondrial gene expression is unchanged versus NPCs; mtDNA copy number and protein mass both increase ~4-fold by 3 weeks.
Methods
- Human BJ iPSC-derived NPCs were differentiated for 1–3 weeks and validated by Sox2/Nestin and MAP2 staining; RNA-seq was performed on two NPC lines with duplicates, and data were mapped with STAR and quantified by FPKM.
- Metabolic profiling used GC-MS for glycolytic/TCA metabolites, Seahorse for OCR, lactate assays, immunoblotting/immunostaining, RT-PCR, ChIP for c-MYC/N-MYC binding, and lenti-shRNA knockdowns of HK2, LDHA, PGC-1α, or ERRγ.
- Direct neuronal conversion from fibroblasts was tested with PTB knockdown or Ngn2/Ascl1 overexpression; mouse neuroprogenitor differentiation and published mouse astrocyte/neuron RNA-seq were used for conservation checks.
Limitations
- The paper states that expression levels of metabolic enzymes do not completely reflect biochemical/physiological activities, and post-translational modifications were not explored.
- The paper notes that mitochondrial structure, dynamics, and matrix calcium were not investigated, and that protein degradation may also downregulate key metabolic enzymes.
- Evident from the text: the main differentiation model relies on human BJ iPSC-derived NPCs, with some key findings validated in mouse cells; 3-week cultures were used as developing neurons, and rare glial cells emerge later, so longer-term neuronal populations were not the primary focus.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
0 of 50 cited sources checked · 0 supported · 0 flagged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mitochondrial mass increases proportionally with neuronal mass growth”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Abstract
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a switch in pyruvate kinase gene splicing from PKM2 to PKM1”
- Also stated in: § Neuron-specific splicing of PKM and OGDH · plain
“NPCs mainly expressed PKM2, whereas neurons expressed PKM1”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Neuron-specific splicing of PKM and OGDH · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression”
- Also stated in: § HK2 and LDHA were off during neuronal differentiation · plain
“HK2 and LDHA mRNAs were about 15% and 25% of those in NPCs, but strikingly, both proteins almost completely disappeared upon differentiation”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § HK2 and LDHA were off during neuronal differentiation · plain
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“whose levels are unchanged compared to NPCs”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically.”
- Also stated in: § HK2 and LDHA were off during neuronal differentiation · plain
“Both c-MYC and N-MYC protein levels decreased significantly, by ~70% and ~85% respectively, once NPCs differentiated into neurons”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § HK2 and LDHA were off during neuronal differentiation · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After 3 weeks of differentiation, a majority (~85%) of cells expressed the neuronal marker MAP2”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Transcription profiling of neuronal differentiation from human NPCs
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the levels of citrate synthase (CS), isocitrate dehydrogenase (IDH2) and succinyl-CoA ligase β subunit (SUCLA2) were constant during differentiation”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > HK2 and LDHA were off during neuronal differentiation
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The basal and maximum OCRs of NPCs were ~82 and 130 (pmoles/min/10 µg), whereas those in 3-week differentiated neurons were ~98 and 183, significantly higher than in NPCs”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Glycolytic and TCA metabolites and oxygen consumption rate in NPCs and neurons
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 43
- Probably not a substantial claim. 17
- The quote only partly states this claim. 1
In the paper
“OGDH, a key enzyme in the TCA cycle, has a novel and conserved neuronal splicing shift, resulting in the loss of a calcium binding motif.”
- Also stated in: § Neuron-specific splicing of PKM and OGDH · plain
“a stretch of 34 amino acids in OGDH1, containing a Ca2+-binding motif (Armstrong et al., 2014), is replaced by 45 amino acids specific to OGDHneu”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Introduction
What the sources say
- Not checked yetcites Armstrong et al., 2014
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Neuron-specific splicing of PKM and OGDH · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the levels of 3-phosphoglyerate (3PG) and pyruvate in neurons dropped to ~52% and 32% of those in NPCs”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Glycolytic and TCA metabolites and oxygen consumption rate in NPCs and neurons
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“citrate was ~32% of that in NPCs, α-ketoglutarate was ~17%, fumarate was ~30%, and malate was ~22%; succinate was relatively higher, at ~62%”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Glycolytic and TCA metabolites and oxygen consumption rate in NPCs and neurons
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“HK2 and LDHA mRNAs were about 15% and 25% of those in NPCs, but strikingly, both proteins almost completely disappeared upon differentiation”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > HK2 and LDHA were off during neuronal differentiation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“both HK2 and LDHA mRNA levels dropped, falling to ~8.5% and ~11% of the level in NPCs, respectively, and, consistently, their protein levels were also greatly decreased”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > HK2 and LDHA were off during neuronal differentiation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“OGDHneu splicing is conserved in mouse neurons, whereas mouse astrocytes, like human astrocytes, only expressed OGDH1”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Neuron-specific splicing of PKM and OGDH
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“OGDH in NPCs (OGDH1) uses exon 4, whereas the isoform in neurons, here called OGDHneu, uses two adjacent exons”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Neuron-specific splicing of PKM and OGDH
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Most of the down-regulated genes were cell cycle related, whereas up-regulated genes were enriched in neuronal function pathways”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Transcription profiling of neuronal differentiation from human NPCs
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the ratio was ~1.61 lactate/glucose for NPCs, while in neurons, it was ~0.35”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Glycolytic and TCA metabolites and oxygen consumption rate in NPCs and neurons
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TCA genes remained at the same level during differentiation; an exception was isocitrate dehydrogenase, IDH2, the mitochondrial isoform of IDH, which dropped nearly 50%”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Gene expression of glycolysis and TCA enzymes during neuronal differentiation
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Except for PDK2, RNA levels of the other three PDKs declined significantly during neuronal differentiation; in contrast, PDP1 RNA levels increased ~2.5 fold at 3 weeks of differentiation”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Gene expression of glycolysis and TCA enzymes during neuronal differentiation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both approaches generated Tuj1-positive neurons after 3 weeks of transduction.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > LDHA is down-regulated in neurons directly converted from fibroblasts
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“no significant difference was found between NPCs and neurons at 1 and 3 weeks, except for SDHB of complex II, which was consistently ~50% lower in neurons (Figure 5C).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Increased neuronal PGC-1α/ERRγ maintained the transcription of glycolysis, TCA and mitochondrial genes
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Indeed, AMPK pT172 was clearly increased at day 4 of neuronal differentiation compared to control, but the phosphorylation returned to a level comparable to control at day 21, when extensive cell death had already occurred (Figure 4I).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Shutoff of aerobic glycolysis is critical for neuronal differentiation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“after the first week, the neuronal mtDNA copy number doubled compared to NPCs, and at 3 weeks was increased to ~four fold.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Increased neuronal PGC-1α/ERRγ maintained the transcription of glycolysis, TCA and mitochondrial genes
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The LDHA signal was clearly detected in GFAP-positive cells with anti-LDHA antibody (Figure 4E) or anti-FLAG antibody staining (Figure 4H), but there was no colocalization with MAP2, a neuronal marker.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Shutoff of aerobic glycolysis is critical for neuronal differentiation
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that PGC-1α was required to maintain the levels of ENO1 and PKM in glycolysis; CS, ACO2, OGDH and SUCLA2 in TCA cycle; TFAM and TFBM1 in mtDNA replication and transcription, and NRF1 (nuclear respiratory factor-1), a key transcription factor that activates nuclear genes encoding respiratory complex subunits (Figure 5F).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Increased neuronal PGC-1α/ERRγ maintained the transcription of glycolysis, TCA and mitochondrial genes
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that during neuronal differentiation, UCP2 expression levels dropped significantly, and in 3-week neurons the UCP2 level was only 20% of that in NPCs (Figure 5—figure supplement 1)”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Molecular changes that define the neuronal energy preference for oxidative phosphorylation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Surprisingly, even though neurons rely on oxidative phosphorylation to generate energy; the expression of TCA and mitochondrial genes is not increased.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Molecular changes that define the neuronal energy preference for oxidative phosphorylation
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Neurons rely on mitochondrial oxidative phosphorylation to meet energy demand.
In the paper
“deletion of lactate dehydrogenase A (LDHA) impairs maintenance and proliferation of hematopoietic stem and progenitor cells (Wang et al., 2014)”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Introduction
What the sources say
- Not checked yetcites Wang et al., 2014
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“PGC-1α knockout mice show obvious neurodegenerative pathology (Lin et al., 2004)”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Introduction
What the sources say
- Not checked yetcites Lin et al., 2004 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating an unknown mechanism linking mitochondrial biogenesis to cell size”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Abstract
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“A pioneering study using embryonic Xenopus retina revealed that neural progenitor cells (NPCs) are less reliant on oxidative phosphorylation for ATP production than are non-dividing differentiated neurons, and the transition from glycolysis to oxidative phosphorylation is tightly coupled to neuronal differentiation”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Introduction
What the sources say
- Not checked yetcites Agathocleous et al., 2012
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Neurons rely on oxidative phosphorylation to meet energy demands.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Only high-quality NPC lines containing more than 90% Sox2 and Nestin double-positive cells were used for experiments.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Transcription profiling of neuronal differentiation from human NPCs
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“The drastic decreases in HK2 and LDHA, the two key enzymes supporting aerobic glycolysis (DeBerardinis and Thompson, 2012; Dang, 2012), are consistent with neurons not having high flux aerobic glycolysis and exhibiting low lactate production.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > HK2 and LDHA were off during neuronal differentiation
What the sources say
- Not checked yetcites DeBerardinis and Thompson, 2012
- Not checked yetcites Dang, 2012
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“MYC, a key transcription factor associated with cell cycle progression, directly activates HK2 and LDHA transcription, and the promoter regions of HK2 and LDHA contain MYC binding sites (5'-CACGTG-3'), also known as E box (Kim et al., 2004).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > HK2 and LDHA were off during neuronal differentiation
What the sources say
- Not checked yetcites Kim et al., 2004
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Denton et al. (2016) also detected this splice form of OGDH in the whole brain tissue and pancreatic islets, calling it LS1, and, importantly, they confirmed that LS1 isoform is insensitive to Ca2+.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Neuron-specific splicing of PKM and OGDH
What the sources say
- Not checked yetcites Denton et al., 2016
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The median sequencing read yield for each sample was ~35 million 100-base reads, of which ~85% were mapped.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Transcription profiling of neuronal differentiation from human NPCs
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“overexpression of PGC-1α in cardiac cells triggers the upregulation of hundreds of genes in glycolysis, TCA and mitochondrial respiratory complexes (Rowe et al., 2010).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Increased neuronal PGC-1α/ERRγ maintained the transcription of glycolysis, TCA and mitochondrial genes
What the sources say
- Not checked yetcites Rowe et al., 2010
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results suggest that neurons cannot tolerate constitutive HK2 and LDHA expression and die during differentiation.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Shutoff of aerobic glycolysis is critical for neuronal differentiation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It appears that although mitochondrial mass increases on a per cell basis, mitochondrial density remains largely unchanged during neuronal differentiation.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Increased neuronal PGC-1α/ERRγ maintained the transcription of glycolysis, TCA and mitochondrial genes
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“A transcriptional circuit, including PGC-1 family coactivators, estrogen-related receptors (ERRs) and nuclear respiratory factor (NRF), is responsible for the transcription of metabolic and mitochondrial genes in multiple tissues, such as heart and skeletal muscle (Scarpulla et al., 2012).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Increased neuronal PGC-1α/ERRγ maintained the transcription of glycolysis, TCA and mitochondrial genes
What the sources say
- Not checked yetcites Scarpulla et al., 2012 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“c-MYC and N-MYC redundantly promote neural progenitor cell proliferation in the developing brain, with the brains of double knockout mice exhibiting profoundly impaired growth (Wey and Knoepfler, 2010).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > HK2 and LDHA were off during neuronal differentiation
What the sources say
- Not checked yetcites Wey and Knoepfler, 2010
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Functional induced neurons (iN) can be generated directly from fibroblasts by forced expression of neural specific transcription factors, a process also called transdifferentiation (Vierbuchen et al., 2010).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > LDHA is down-regulated in neurons directly converted from fibroblasts
What the sources say
- Not checked yetcites Vierbuchen et al., 2010 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“PGC-1α is induced in the neonatal mouse heart concurrent with the increase of mitochondrial energy-producing capacity (Lehman et al., 2000).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Increased neuronal PGC-1α/ERRγ maintained the transcription of glycolysis, TCA and mitochondrial genes
What the sources say
- Not checked yetcites Lehman et al., 2000 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“PGC-1α not only stimulates the induction of NRF1, but also binds to and coactivates the transcriptional function of NRF1 in muscle cells (Wu et al., 1999).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Result > Increased neuronal PGC-1α/ERRγ maintained the transcription of glycolysis, TCA and mitochondrial genes
What the sources say
- Not checked yetcites Wu et al., 1999
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“UCP2 is critical for maintaining stem cell glycolytic metabolism, and its level decreases during differentiation (Zhang et al., 2011; Yu et al., 2013).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Molecular changes that define the neuronal energy preference for oxidative phosphorylation
What the sources say
- Not checked yetcites Zhang et al., 2011
- Not checked yetcites Yu et al., 2013
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“MILS neurons also have very low expression of HK2 and LDHA, and do not exhibit a significant increase in mitochondrial density (Zheng et al., 2016).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Molecular changes that define the neuronal energy preference for oxidative phosphorylation
What the sources say
- Not checked yetcites Zheng et al., 2016
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The critical role of LDHA in aerobic glycolysis has been proven in cancer cells, and LDHA depletion greatly decreases aerobic glycolysis and increases mitochondrial OXPHOS activity (Fantin et al., 2006).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Molecular changes that define the neuronal energy preference for oxidative phosphorylation
What the sources say
- Not checked yetcites Fantin et al., 2006
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It appears that neurons cannot use aerobic glycolysis or mitochondrial biogenesis to compensate for energy shortage.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Molecular changes that define the neuronal energy preference for oxidative phosphorylation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The A4 isozyme kinetically favors the conversion from pyruvate to lactate, while the B4 isozyme prefer converting lactate to pyruvate (Cahn et al., 1962).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Molecular changes that define the neuronal energy preference for oxidative phosphorylation
What the sources say
- Not checked yetcites Cahn et al., 1962
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In an iPSC-based disease model of maternally inherited Leign syndrome (MILS), an early childhood neurodegenerative disease due to ATP synthase defect, we found that MILS neurons but not their NPCs show severe energy deficiency; MILS NPCs generate more lactate than healthy control NPCs.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Molecular changes that define the neuronal energy preference for oxidative phosphorylation
What the sources say
- Not checked yetcites Zheng et al., 2016
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Glucose transporter levels dramatically decrease in neurons, which limits glucose uptake and the production of glycolytic pyruvate.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Shut-off of aerobic glycolysis is critical for neuronal differentiation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fourth, the decrease in expression of PDKs and the increase in PDPs may result in more active pyruvate dehydrogenase complexes (PDC), as demonstrated by decreased phosphorylation at Ser 300 of PDH E1 alpha protein (PDHA1), promoting pyruvate entry into the TCA cycle.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Molecular changes that define the neuronal energy preference for oxidative phosphorylation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“mitochondrial structure (cristae organization and size), dynamics (fusion and fission) and calcium concentration in the mitochondrial matrix are all involved in mitochondrial energy metabolism (Mishra and Chan, 2014).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Molecular changes that define the neuronal energy preference for oxidative phosphorylation
What the sources say
- Not checked yetcites Mishra and Chan, 2014
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Third, the decreased expression of HK2, and the GLUT1 and GLUT3 glucose transporters reduce glucose entry, terminating high flux glycolysis.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Molecular changes that define the neuronal energy preference for oxidative phosphorylation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For each time point, two experimental duplicates were used for each independent NPC line and its differentiated neurons.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Materials and methods > RNA sequencing
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“in a high-throughput screen to identify small molecules interfering with mitochondrial abundance, hundreds of compounds were found to be capable of changing the cellular mitochondrial content; the majority of them also change cell size accordingly (Kitami et al., 2012)”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Metabolic and mitochondrial gene transcription control in proliferating and post-mitotic differentiated cells
What the sources say
- Not checked yetcites Kitami et al., 2012
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This step is critical for the purity of NPCs; only colonies (type 4) showing sufficient maturity as described in Figure 1—figure supplement 2 were picked.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Materials and methods > Establishment of NPCs and neuronal differentiation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“blocking neuronal oxidative utilization of lactate affects neuronal survival and even memory formation (Suzuki et al., 2011; Lee et al., 2012).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Shut-off of aerobic glycolysis is critical for neuronal differentiation
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“c-MYC activation in the myocardium of adult mice induces mitochondrial biogenesis and glycolysis but reduces PGC-1α level (Ahuja et al., 2010).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Metabolic and mitochondrial gene transcription control in proliferating and post-mitotic differentiated cells
What the sources say
- Not checked yetcites Ahuja et al., 2010
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“RNA-seq experiments were performed with two NPC lines established from independent iPSC clones.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Materials and methods > RNA sequencing
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“only samples with RIN greater than 8.5 were used for library preparation.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Materials and methods > RNA sequencing
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“E2F also upregulates mitochondrial genes, a function conserved from flies to mammals (Ambrus et al., 2013).”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Metabolic and mitochondrial gene transcription control in proliferating and post-mitotic differentiated cells
What the sources say
- Not checked yetcites Ambrus et al., 2013
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that glycolytic pyruvate deficiency is a major cause of death.”
§ Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation > Discussion > Shut-off of aerobic glycolysis is critical for neuronal differentiation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
The paper relies on this without support.
Little is known about the molecular basis of neurons' preference for oxidative phosphorylation or neuronal metabolic responses to energy crisis and their implications for disease progression.
“Little is known about the molecular basis of neurons’ preference for oxidative phosphorylation, or neuronal metabolic responses to the energy crisis and their implications for disease progression.”
The paper relies on this without support.
Neurons rely on oxidative phosphorylation to meet energy demands.
“Neurons rely on oxidative phosphorylation to meet energy demands.”
The paper relies on this without support.
Neurons rely on mitochondrial oxidative phosphorylation to meet energy demand.
“Neurons rely on mitochondrial oxidative phosphorylation to meet energy demand.”
The paper relies on this without support.
Aerobic glycolysis diverts pyruvate from mitochondrial oxidative phosphorylation for energy production by converting it into secreted lactate.
“As aerobic glycolysis diverts pyruvate from mitochondrial oxidative phosphorylation for energy production by converting it into secreted lactate”
The paper relies on this without support.
HK1 is still expressed in neurons.
“HK1 is still expressed in neurons”
The paper relies on this without support.
In proliferating NPCs, mitochondria are used for generation of biosynthetic precursors and mitochondria themselves have to be duplicated for daughter cells.
“mitochondria are used for generation of biosynthetic precursors in these proliferating cells, and mitochondria themselves have to be duplicated for daughter cells.”
The paper relies on this without support.
The expression levels of metabolic enzymes alone do not completely reflect their biochemical/physiological activities.
“the expression levels of metabolic enzymes alone do not completely reflect their biochemical/physiological activities”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“In multiple tissue contexts, adult stem cells have been found to primarily engage in aerobic glycolysis.”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [205]
In the citing paper
“Upon lineage commitment and differentiation, however, cells increase their oxidation of pyruvate in the TCA cycle and display enhanced OXPHOS (203, 204, 205).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [205]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
NPC passage differs between the results and Figure 3 caption
MinorThe results say the HK2 and LDHA knockdown experiment used passage-3 NPCs, while the Figure 3C caption says passage 2.
“BJ NPC cells at passage 3 were infected with lenti-shRNAs targeting HK2 or LDHA.”
“NPCs at early passage (P2) were seeded in 24-well plates one day before infection.”
Figure 1 caption reverses the TCA and PDH panel assignments
MinorIn the caption's ordered list, panel H corresponds to TCA and panel I to PDH. The results instead cite panel I for TCA genes and panel H for PDH-complex genes.
“(G, H, I and J) Relative expression levels of the key metabolic genes in glycolysis, tricarboxylic acid cycle (TCA), pyruvate dehydrogenase (PDH) complex and pentose phosphate pathway.”
“Expression of the genes encoding the subunits of PDC itself, including PDHA1, PDHB, PDHX, DLAT, and DLD, showed no significant changes (Figure 1H).”
Citations
Cites
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709 · cited 3×
“RNA-seq reactions were done on an Illumina HiSeq 2500 system (Illumina, San Diego, CA) and the sequenced reads were mapped to an annotated human genome (version GRch37/hg19) using STAR (Dobin et al., 2013).”
BackgroundMethodUnderstanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197 · cited 1×
“Most cancer cells use aerobic glycolysis to generate energy, a phenomenon called the Warburg effect, in which a large fraction of glycolytic pyruvate is converted into lactate (Vander Heiden et al., 2009).”
BackgroundTrapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., Salzberg, S. L., Wold, B. J., & Pachter, L. (2010) · Nature Biotechnology · doi:10.1038/nbt.1621 · Cited by 15,556
Robinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G., & Mesirov, J. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1754 · Cited by 15,390 · cited 3×
“…whether changes in alternative mRNA splicing occurred in glycolysis, TCA and mitochondrial respiratory complex genes during neuronal differentiation, the distributions of exonic RNA-seq reads were manually compared between NPCs and neurons using Integrative Genomics Viewer (Robinson et al., 2011).”
MethodInfluentialTrapnell, C., Roberts, A., Goff, L. A., Pertea, G. M., Kim, D., Kelley, D. R., Pimentel, H., Salzberg, S. L., Rinn, J. L., & Pachter, L. S. (2012) · Nature Protocols · doi:10.1038/nprot.2012.016 · Cited by 12,145 · cited 1×
“The sequencing reads were mapped to a human reference genome by STAR and assembled with Cufflinks (Dobin et al., 2013; Trapnell et al., 2012).”
MethodMitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · cited 2×
“This result was consistent with a recent finding that mouse neurons exclusively expressed PKM1, whereas astrocytes only expressed PKM2 (Zhang et al., 2014).”
ResultWu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80611-x · Cited by 4,139 · cited 2×
“PGC-1a not only stimulates the induction of NRF1, but also binds to and coactivates the transcriptional function of NRF1 in muscle cells (Wu et al., 1999).”
BackgroundChronic systemic pesticide exposure reproduces features of Parkinson's disease
Betarbet, R. S., Sherer, T., MacKenzie, G. M., Garcia‐Osuna, M., Panov, A. V., & Greenamyre, J. T. (2000) · Nature Neuroscience · doi:10.1038/81834 · Cited by 3,770 · cited 1×
“For example, chronic exposure of the brain to the lipophilic pesticide rotenone causes dopaminergic neuron degeneration (Betarbet et al., 2000).”
BackgroundHypoxia-inducible factors in physiology and medicine
Semenza, G. L. (2012) · Cell · doi:10.1016/j.cell.2012.01.021 · Cited by 3,645 · cited 1×
“Moreover, under low oxygen condition, the transcription of glycolytic genes is upregu- lated by hypoxia-inducible factor (HIF), and increased glycolytic ATP produced by enhanced glyco- lytic flux can partially supply cellular energy demands (Iyer et al., 1998; Seagroves et al., 2001; Semenza, 2012).”
Background
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–200 of 666
The Role of DJ-1 in Cellular Metabolism and Pathophysiological Implications for Parkinson’s Disease
Mencke, P., Boussaad, I., Romano, C., Kitami, T., Linster, C. L., & Krüger, R. (2021) · Cells · doi:10.3390/cells10020347 · Cited by 64
Weak neuronal glycolysis sustains cognition and organismal fitness
Jiménez-Blasco, D., Agulla, J., Lapresa, R., Macia, M. G., Bobo-Jiménez, V., García-Rodríguez, D., Manjarrés-Raza, I., Fernández, E., Jeanson, Y., Khoury, S., et al. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01049-0 · Cited by 65
The potential role of mitochondria in the microbiota-gut-brain axis: Implications for brain health
Qiao, L., Yang, G., Wang, P., & Xu, C. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107434 · Cited by 73
Zuberi, Z., Eeza, M. N. H., Matysik, J., et al. (2019) · Toxins · doi:10.3390/toxins11050258 · Cited by 61
“Anaerobic glycolysis is, in fact, an essential energetic pathway during early embryonic stages, and a requisite shift in metabolism from anaerobic glycolysis to oxidative phosphorylation accompanies programmed embryo development [46].”
Background‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders
Nakamura, T., & Lipton, S. A. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.10.004 · Cited by 60
“Additionally, during differentiation from neuronal progenitor cells (using predominantly glycolysis) to neurons, expression of hexokinase and lactate dehydrogenase A (LDHA), both of which play critical roles in glycolysis, dramatically declines [23].”
BackgroundThe requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage
Jun, S., Mahesula, S., Mathews, T. P., Martin-Sandoval, M. S., Zhao, Z., Piskounova, E., & Agathocleous, M. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.07.016 · Cited by 58
Differentiation but not ALS mutations in FUS rewires motor neuron metabolism
Vandoorne, T., Veys, K., Guo, W., Sicart, A., Vints, K., Swijsen, A., Moisse, M., Eelen, G., Gounko, N. V., Fumagalli, L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12099-4 · Cited by 59
Bifari, F., Dolci, S., Bottani, E., Pino, A., Chio, M. D., Zorzin, S., Ragni, M., Zamfir, R. G., Brunetti, D., Bardelli, D., et al. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104863 · Cited by 56
FASN-dependent de novo lipogenesis is required for brain development
Gonzalez-Bohorquez, D., López, I. M. G., Jaeger, B. N., Pfammatter, S., Bowers, M., Semenkovich, C. F., & Jessberger, S. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2112040119 · Cited by 60
Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome
Carosso, G. A., Boukas, L., Augustin, J. J., Nguyen, H. N., Winer, B. L., Cannon, G. H., Robertson, J. D., Zhang, L., Hansen, K. D., Goff, L. A., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.129375 · Cited by 57
“Mounting evidence tightly links metabolic rewiring (19) and hypoxic states in the DG (20, 21) to cell-intrinsic regulation of NSPC maintenance.”
BackgroundNext‐generation disease modeling with direct conversion: a new path to old neurons
Traxler, L., Edenhofer, F., & Mertens, J. (2019) · FEBS Letters · doi:10.1002/1873-3468.13678 · Cited by 57
Self-citationAging membranes: Unexplored functions for lipids in the lifespan of the central nervous system
Skowronska‐Krawczyk, D., & Budin, I. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.110817 · Cited by 56
Metabolism navigates neural cell fate in development, aging and neurodegeneration
Traxler, L., Lagerwall, J., Eichhorner, S., Stefanoni, D., D’Alessandro, A., & Mertens, J. (2021) · Disease Models & Mechanisms · doi:10.1242/dmm.048993 · Cited by 59
Self-citationRedox Signaling Mechanisms in Nervous System Development
Olguín‐Albuerne, M., & Morán, J. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7284 · Cited by 59
“Conversely, inducing constitutive expression of hexokinase 2 and lactate dehydrogenase A results in reduced pyruvate entry into the TCA cycle, which causes massive cell death only in the differentiating neurons (179).”
InfluentialMitochondria in Developmental and Adult Neurogenesis
Arrázola, M. S., Andraini, T., Szelechowski, M., Moulédous, L., Pelloquin, L., Davezac, N., Belenguer, P., Rampon, C., & Miquel, M. (2018) · Neurotoxicity Research · doi:10.1007/s12640-018-9942-y · Cited by 57
Wu, X., Fan, Y., Wang, K., et al. (2024) · 中国科学通报：英文版 · doi:10.1016/j.scib.2024.02.008 · Cited by 55
Su, Y., Cao, N., Zhang, D., & Wang, M. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102248 · Cited by 58
Neural Stem Cell Plasticity: Advantages in Therapy for the Injured Central Nervous System
Ottoboni, L., Merlini, A., & Martino, G. (2017) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2017.00052 · Cited by 56
“In the quiescent state, NSC mitochondria are quite immature with globular shape, do not depend much for energy on oxidative phosphorylation (OXPHOS), rather on glycolysis, with high lactate production (Zheng et al., 2016).”
BackgroundDirect Neuronal Reprogramming: Bridging the Gap Between Basic Science and Clinical Application
Vasan, L., Park, E., David, L. A., Fleming, T., & Schuurmans, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.681087 · Cited by 61
Singh, T., Jiao, Y., Ferrando, L. M., Yablonska, S., Li, F., Horoszko, E. C., Lacomis, D., Friedlander, R. M., & Carlisle, D. L. (2021) · Scientific Reports · doi:10.1038/s41598-021-97928-7 · Cited by 55
Romero-Morales, A. I., Robertson, G. L., Rastogi, A., Rasmussen, M. L., Temuri, H., McElroy, G. S., Chakrabarty, R. P., Hsu, L., Almonacid, P. M., Millis, B. A., et al. (2022) · Development · doi:10.1242/dev.199914 · Cited by 58
Transcriptome Analysis of Small Molecule–Mediated Astrocyte-to-Neuron Reprogramming
Ma, N., Yin, J.-C., & Chen, G. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00082 · Cited by 58
Coelho, P., Fão, L., Mota, S. I., & Rego, A. C. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101667 · Cited by 62
Adult neural stem cell fate is determined by thyroid hormone activation of mitochondrial metabolism
Gothié, J. M., Sébillot, A., Luongo, C., Legendre, M., Van, C. N., Blay, K. L., Perret-Jeanneret, M., Remaud, S., & DEMENEIX, B. A. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.08.003 · Cited by 53
“To inhibit ATP synthase and OXPHOS, oligomycin (Sigma) 1 mM was added to culture medium during cell differentiation.”
BackgroundInfluentialJing, R., Corbett, J., Cai, J., Beeson, G. C., Beeson, C., Chan, S. S. L., Dimmock, D., Lazcares, L., Geurts, A. M., Lemasters, J. J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.036 · Cited by 58
“The high metabolic activity of hepatocytes makes them especially dependent on efficient mitochondrial function to provide ATP, while iPSCs rely largely on glycolysis as the source of energy production (Folmes et al., 2011; Zheng et al., 2016).”
BackgroundMartirosian, V., Deshpande, K., Zhou, H., Shen, K., Smith, K. S., Northcott, P. A., Lin, M. P., Stepanosyan, V., Das, D., Remšík, J., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109302 · Cited by 55
“Therefore, we hypothesized that metabolic diversity must also be present, considering that developing neural cells undergo metabolic changes as they differentiate (Zheng et al., 2016).”
Thyroid hormone regulation of neural stem cell fate: From development to ageing
Gothié, J. M., Vancamp, P., DEMENEIX, B. A., & Remaud, S. (2019) · Acta Physiologica · doi:10.1111/apha.13316 · Cited by 54
Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease
Kaya, E., Smith, D. A., Smith, C., Boland, B., Strupp, M. L., & Platt, F. M. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9041050 · Cited by 52
“In accordance with this, we found that PDH, a key indicator of aerobic respiration [48], was more active (55.”
BackgroundWei, Z., Xia, J., Li, J., Cai, J., Shan, J., Zhang, C., Zhang, L., Wang, T., Qian, C., & Liu, L. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.76704 · Cited by 52
Neural stem cell metabolism revisited: a critical role for mitochondria
Scandella, V., Petrelli, F., Moore, D. L., Braun, S. M. G., & Knobloch, M. (2023) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2023.05.008 · Cited by 55
“A similar metabolic regulation occurs in muscle stem cells, in which glycolysis increases after their activation [100,101], which is also the case for other adult stem cells [44,102].”
BackgroundAgnihotri, S. K., Shen, R., Li, J., Gao, X., & Büeler, H. (2017) · The FASEB Journal · doi:10.1096/fj.201600960rr · Cited by 50
“Preventing this metabolic shift byconstitutiveoverexpressionofglycolytic key enzymes causes neuronal death (58).”
BackgroundUittenbogaard, M. N., Brantner, C. A., & Chiaramello, A. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0396-1 · Cited by 51
Metabolism as an early predictor of DPSCs aging
Macrin, D., Alghadeer, A., Zhao, Y. T., Miklas, J. W., Hussein, A. M., Detraux, D., Robitaille, A. M., Madan, A., Moon, R. T., Wang, Y., et al. (2019) · Scientific Reports · doi:10.1038/s41598-018-37489-4 · Cited by 49
Comparative approaches to understanding thyroid hormone regulation of neurogenesis
Gothié, J. M., DEMENEIX, B. A., & Remaud, S. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.05.020 · Cited by 52
“Furthermore, stem cells display metabolic features of glycosylation, in contrast with differentiated cells, that mainly rely on oxidative phosphorylation (OXPHOS) (Vander Heiden et al., 2009; Zheng et al., 2016).”
BackgroundIqbal, M. A., Siddiqui, S. I., Rehman, A. U., Siddiqui, F. A., Singh, P. K., Kumar, B., & Saluja, D. (2021) · Molecular Oncology · doi:10.1002/1878-0261.12894 · Cited by 46
“Moreover, metabolic changes are crucial in determining cellular fate and differentiation [25,26].”
BackgroundCell Metabolic Alterations due to Mcph1 Mutation in Microcephaly
Journiac, N., Gilabert‐Juan, J., Cipriani, S., Bénit, P., Liu, X., Jacquier, S., Faivre, V., Delahaye‐Duriez, A., Csaba, Z., Hourcade, T., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.070 · Cited by 48
Griffiths, K. K., Wang, A., Wang, L., Tracey, M., Kleiner, G., Quinzii, C. M., Sun, L., Yang, G., Perez‐Zoghbi, J. F., Licznerski, P., et al. (2018) · The FASEB Journal · doi:10.1096/fj.202000283rr · Cited by 50
Coenzyme Q redox signalling and longevity
Scialò, F., & Sanz, A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.01.018 · Cited by 48
Mitochondrial dysfunction in cognitive neurodevelopmental disorders: Cause or effect?
Anitha, A., Thanseem, I., Iype, M., & Thomas, S. V. (2023) · Mitochondrion · doi:10.1016/j.mito.2023.01.002 · Cited by 47
Roy, U., Conklin, L., Schiller, J., Matysik, J., Berry, J. P., & Alia, A. (2017) · Scientific Reports · doi:10.1038/s41598-017-17409-8 · Cited by 46
siVAE: interpretable deep generative models for single-cell transcriptomes
Choi, Y., Li, R., & Quon, G. (2023) · Genome biology · doi:10.1186/s13059-023-02850-y · Cited by 51
Oligodendrocyte-derived transcellular signaling regulates axonal energy metabolism
Li, S., & Sheng, Z. (2023) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2023.102722 · Cited by 50
Ludikhuize, M. C., & Colman, M. J. R. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8126 · Cited by 45
“In line with this, neuronal differentiation is accompanied by increased expression of glycolytic enzymes, a shift from pyruvate kinase M2 (PKM2) to PKM1 expression, activation of pyruvate dehydrogenase (PDH), and an increase in mitochondrial mass and respiration (51, 194).”
InfluentialLone, A., Harris, R. A., Singh, O., Betts, D. H., & Cumming, R. C. (2018) · Scientific Reports · doi:10.1038/s41598-018-35114-y · Cited by 44
Mitochondria regulate intestinal stem cell proliferation and epithelial homeostasis through FOXO
Zhang, F., Pirooznia, M., & Xu, H. (2020) · Molecular Biology of the Cell · doi:10.1091/mbc.e19-10-0560 · Cited by 43
NAAA-regulated lipid signaling governs the transition from acute to chronic pain
Fotio, Y., Jung, K., Palese, F., Obenaus, A., Tagne, A. M., Lin, L., Rashid, T. I., Pacheco, R., Jullienne, A., Ramirez, J., et al. (2021) · Science Advances · doi:10.1126/sciadv.abi8834 · Cited by 40
Understanding the Contribution of Lactate Metabolism in Cancer Progress: A Perspective from Isomers
Cai, M., Wan, J., Cai, K., Song, H., Wang, Y., Sun, W., & Hu, J. (2022) · Cancers · doi:10.3390/cancers15010087 · Cited by 47
“In carcinoma cells, lactate dehydrogenase isoform A (LDHA) preferentially converts synthetic pyruvate to L-lactate by removing hydrogen from the NADH molecule in the final step of the glycolytic pathway [34], thereby regenerating NAD+ to maintain glycolysis [35,36], which serves as a substrate for GAPDH [37].”
BackgroundČervenka, J., Tylečková, J., Skalníková, H. K., Kepková, K. V., Poliakh, I., Valeková, I., Pfeiferová, L., Kolář, M., Vaškovičová, M., Pánková, T., et al. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.612560 · Cited by 46
“Currently, 40 studies employing NSCs/NPCs are Active or Completed according to ClinicalTrials.gov.”
BackgroundInfluentialCiarpella, F., Zamfir, R. G., Campanelli, A., Ren, E., Pedrotti, G., Bottani, E., Borioli, A., Caron, D., Chio, M. D., Dolci, S., et al. (2021) · iScience · doi:10.1016/j.isci.2021.103438 · Cited by 47
“Mitochondria are mainly responsible for energy production through the OXPHOS process that is upregulated in mature neurons compared to NSCs (Beckervordersandforth et al., 2017; Bifari et al., 2020; Lorenz et al., 2017; Martano et al., 2019; Zheng et al., 2016; Inak et al., 2021).”
BackgroundZhang, L., Zhao, Q., Cang, H., Wang, Z., Hu, X., Pan, R., Yang, Y., & Chen, Y. (2022) · Advanced Science · doi:10.1002/advs.202105811 · Cited by 42
Cabello-Rivera, D., Sarmiento‐Soto, H., López‐Barneo, J., & Muñoz-Cabello, A. M. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00664 · Cited by 42
“…of Hospital Virgen del Rocío/Institute of Biomedicine of Seville (reference number 22-09-15-332). hGFAP-NDUFS2 knockout mice (Ndufs2flox/− hGFAP-Cre genotype) were generated by breeding the Ndufs2flox strain (Fernández-Agüera et al., 2015) with the transgenic strain hGFAP-Cre (Zhuo et al., 2001).”
MethodModeling mitochondrial DNA diseases: from base editing to pluripotent stem‐cell‐derived organoids
Tolle, I., Tiranti, V., & Prigione, A. (2023) · EMBO Reports · doi:10.15252/embr.202255678 · Cited by 43
“Differentiated cells from iPSCs do in fact show reliance on OXPHOS metabolism (Chung et al , 2007; Zheng et al , 2016b; Cliff & Dalton, 2017; Tanosaki et al , 2021).”
Patient-Derived Midbrain Organoids to Explore the Molecular Basis of Parkinson's Disease
Galet, B., Cheval, H., & Ravassard, P. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.01005 · Cited by 47
“Indeed, such composition may be partly responsible for the cellular stress and differentiation defects observed in several brain organoid cultures (94), as the abnormally high levels of glucose used in the vast majority of hMO protocols are known to impair the normal metabolic reprogramming of neural progenitor cells…”
BackgroundNAD Depletion Mediates Cytotoxicity in Human Neurons With Autophagy Deficiency
Sun, C., Seranova, E., Cohen, M. A., Chipara, M., Roberts, J., Astuti, D., Palhegyi, A. M., Acharjee, A., Sedlackova, L., Kataura, T., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2023.112372 · Cited by 43
Wu, D., Sun, J. K., & Chow, H. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002559 · Cited by 50
Early Life Stress and Metabolic Plasticity of Brain Cells: Impact on Neurogenesis and Angiogenesis
Salmina, A. B., Gorina, Y. V., Komleva, Y. K., Panina, Y. A., Malinovskaya, N. A., & Lopatina, O. L. (2021) · Biomedicines · doi:10.3390/biomedicines9091092 · Cited by 42
SQSTM1/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation
Calvo‐Garrido, J., Maffezzini, C., Rosenberger, F. A., Clemente, P., Uhlin, E., Kele, M., Stranneheim, H., Lesko, N., Bruhn, H., Svenningsson, P., et al. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.01.023 · Cited by 44
“Recent work from Zheng and colleagues suggests that neuronal progenitor cells initiate a metabolic shift from glycolytic to a more OXPHOS metabolism during differentiation (Zheng et al., 2016).”
BackgroundInfluentialType 3 diabetes and metabolic reprogramming of brain neurons: causes and therapeutic strategies
Meng, X., Zhang, H., Zhao, Z., Li, S., Zhang, X., Guo, R., Li, H., Yuan, Y., Li, W., Song, Q., et al. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01101-z · Cited by 47
Stem Cell Metabolism in Cancer and Healthy Tissues: Pyruvate in the Limelight
Corbet, C. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00958 · Cited by 39
“Expressions of hexokinase 2 (HK2), LDHA and the specific isoform PKM2 were found to support the maintenance of the pools of HSCs and NSCs (Wang et al., 2014; Zheng et al., 2016).”
InfluentialLopes, C., Tang, Y., Anjo, S. I., Manadas, B. J., Onofre, I., de Almeida, L. P., Daley, G. Q., Schlaeger, T. M., & Rego, A. C. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.576592 · Cited by 40
Yanardag, S., & Pugacheva, E. N. (2021) · Cells · doi:10.3390/cells10061428 · Cited by 40
“High glycolytic metabolism is needed to maintain pluripotency but, as stem cells mature and differentiate, they switch towards oxidative phosphorylation [84] in an mTOR-dependent manner.”
BackgroundPPARs and Energy Metabolism Adaptation during Neurogenesis and Neuronal Maturation
d’Angelo, M., Antonosante, A., Castelli, V., Catanesi, M., Moorthy, N. K., Iannotta, D., Cimini, A., & Benedetti, E. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071869 · Cited by 37
Richard, A., Vallin, E., Romestaing, C., Roussel, D., Gandrillon, O., & Gonin-Giraud, S. (2019) · PLoS ONE · doi:10.1371/journal.pone.0221472 · Cited by 38
“It has also been demonstrated that 11 preventing the shutting down of the glycolytic pathway was detrimental for neuronal 12 differentiation [4].”
BackgroundQi, G., Mi, Y., & Yin, F. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2019.01531 · Cited by 38
“…primarily rely on mitochondrial oxidative phosphorylation (OXPHOS) for energy transduction and possess low glycolytic capacity due to the suppression of a key glycolysis enzyme 6-phosphofructo2-kinase/fructose-2,6-bisphosphatase (PFKFB) (Schönfeld and Reiser, 2013; Zheng et al., 2016; Figure 1).”
BackgroundRodrigues, D. C., Harvey, E. M., Suraj, R., Erickson, S. L., Mohammad, L., Ren, M., Liu, H., He, G., Kaplan, D. R., Ellis, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15941-2 · Cited by 39
Louadi, Z., Elkjaer, M. L., Klug, M., Lio, C. T., Fenn, A. M., Illés, Z., Bongiovanni, D., Baumbach, J., Kacprowski, T., List, M., et al. (2021) · Genome biology · doi:10.1186/s13059-021-02538-1 · Cited by 36
Schizophrenia, a disease of impaired dynamic metabolic flexibility: A new mechanistic framework
Sarnyai, Z., & Ben‐Shachar, D. (2024) · Psychiatry Research · doi:10.1016/j.psychres.2024.116220 · Cited by 39
“As NSC differentiate into neurons, glucose metabolism switches almost exclusively to OXPHOS, which seems to be required for Z. Sarnyai and D. Ben-Shachar Psychiatry Research 342 (2024) neuronal differentiation (Zheng et al. 2016).”
Background(Re)building the nervous system: A review of neuron–glia interactions from development to disease
Demmings, M. D., Chagas, L. D. S., Traetta, M. E., Rodrigues, R. S., Acutain, M. F., Barykin, E. P., Datusalia, A. K., German‐Castelan, L., Mattera, V. S., Mazengenya, P., et al. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16258 · Cited by 44
“While glycolysis provides a source of energy, mature neurons rely mainly on oxidative phosphorylation (OXPHOS) to meet their high energetic demands (Hertz et al., 2007; Sokoloff et al., 1977; Whitesell et al., 1995 ; Zheng et al., 2016 ).”
Stage-specific metabolic features of differentiating neurons: Implications for toxicant sensitivity
Delp, J., Gutbier, S., Cerff, M., Zasada, C., Niedenführ, S., Zhao, L., Smirnova, L., Härtung, T., Borlinghaus, H., Schreiber, F., et al. (2017) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2017.12.013 · Cited by 38
Chumarina, M., Russ, K., Azevedo, C., Heuer, A., Pihl, M., Collin, A., Frostner, E. Å., Elmér, E., Hyttel, P., Cappelletti, G., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0863-7 · Cited by 38
The role of the NMD factor UPF3B in olfactory sensory neurons
Tan, K., Jones, S. H., Lake, B. B., Chousal, J. N., Shum, E. Y., Zhang, L., Chen, S., Sohni, A., Pandya, S., Gallo, R. L., et al. (2020) · eLife · doi:10.7554/elife.57525 · Cited by 39
Dietary interventions as regulators of stem cell behavior in homeostasis and diseasePreprint
Novak, J. S. S., Baksh, S. C., & Fuchs, E. V. (2021) · Genes & Development · doi:10.1101/gad.346973.120 · Cited by 38
“Similarly, inhibition of the glycolytic enzyme hexokinase (HK2) and lactate dehydrogenase (LDH) during normoxia resulted in proliferation defects in neural progenitor cells (Zheng et al. 2016).”
BackgroundThe brain serotonin system in autism
Rodnyy, A. Y., Kondaurova, E. M., Tsybko, A. S., Popova, N. K., Kudlay, D. A., & Naumenko, V. S. (2023) · Reviews in the Neurosciences · doi:10.1515/revneuro-2023-0055 · Cited by 39
Lisowski, P., Lickfett, S., Rybak‐Wolf, A., Menacho, C., Le, S., Pentimalli, T. M., Notopoulou, S., Dykstra, W., Oehler, D., López-Calcerrada, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51216-w · Cited by 51
Improvement of neuronal differentiation by carbon monoxide: Role of pentose phosphate pathway
Almeida, A. S., Soares, N. L., Sequeira, C. O., Pereira, S. A., Sonnewald, U., & Vieira, H. L. A. (2018) · Redox Biology · doi:10.1016/j.redox.2018.05.004 · Cited by 36
“Moreover, neuronal metabolism relies mostly on oxidative phosphorylation and PPP is very active in neurons [17,53,54].”
BackgroundHori, S., Hiramuki, Y., Nishimura, D., Sato, F., & Sehara‐Fujisawa, A. (2019) · The FASEB Journal · doi:10.1096/fj.201802479r · Cited by 37
“Induced pluripotent stem cell–derived neural progenitor cell differentiation into neurons is also accompanied by the glycolysis-to-TCA or -oxphos transition (11).”
BackgroundD’Aloia, A., Pastori, V., Blasa, S., Campioni, G., Peri, F., Sacco, E., Ceriani, M., Lecchi, M., & Costa, B. (2024) · Cell Death Discovery · doi:10.1038/s41420-023-01790-7 · Cited by 36
“In all the protocols described above, the culture medium was changed every 3 – 4 days by removing 30% of the total volume and adding fresh medium corresponding to 40% of the total volume.”
Li, S., Li, W., Yuan, J., Bullova, P., Wu, J., Zhang, X., Liu, Y., Plescher, M., Rodríguez, J., Bedoya-Reina, O. C., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00593-x · Cited by 36
“coupled to differentiation, although the exact molecular basis underlying the transition is unknown 34,35 .”
Andreyev, A. Y., Yang, H., Doulias, P., Dolatabadi, N., Zhang, X., Luevanos, M., Blanco, M., Baal, C., Putra, I., Nakamura, T., et al. (2024) · Advanced Science · doi:10.1002/advs.202306469 · Cited by 35
Role of Cell Metabolism and Mitochondrial Function During Adult Neurogenesis
Almeida, A. S., & Vieira, H. L. A. (2016) · Neurochemical Research · doi:10.1007/s11064-016-2150-3 · Cited by 35
“Also, PGC-1α and estrogen-related receptor gamma (ERRγ) increase significantly during differentiation, which is required for maintaining the expression of TCA cycle and mitochondrial respiratory complex genes [60].”
BackgroundAugustyniak, J., Lenart, J., Zychowicz, M., Stępień, P. P., & Bużańska, L. (2017) · Biogerontology · doi:10.1007/s10522-017-9718-4 · Cited by 34
“Differentiation of hiPSC into neural progenitors is associated with the metabolic switch from glycolysis to oxidative phosphorylation (OXPHOS) and is correlated with an increase in the number of mitochondria (Zheng et al. 2016).”
Wang, J., Huang, Y., Cai, J., Ke, Q., Xiao, J., Huang, W., Li, H., Qiu, Y., Wang, Y., Zhang, B., et al. (2018) · Stem Cells · doi:10.1002/stem.2769 · Cited by 35
Zhang, Y., Yan, X.-Z., Xu, S., Pang, Z., Li, L., Yang, Y., Fan, Y., Wang, Z., Yu, X., Guo, C., et al. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00262 · Cited by 35
Krantz, S., Kim, Y.-M., Srivastava, S., Leasure, J. W., Tóth, P. T., Marsboom, G., & Rehman, J. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101410 · Cited by 34
“The recognition that metabolic reprogramming is an essential feature of stem cell differentiation (8, 9) raises the important question of how mitochondria in pluripotent stem cells are reprogrammed during differentiation.”
BackgroundSelf-citationSwain, M., Soman, S. K., Tapia, K., Dagda, R. Y., & Dagda, R. K. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15945 · Cited by 41
Reverse engineering human brain evolution using organoid models
Mostajo-Radji, M. A., Schmitz, M. T., Torres, S., & Pollen, A. A. (2019) · Brain Research · doi:10.1016/j.brainres.2019.146582 · Cited by 36
“These glycolysis signatures extend to newborn neurons that normally undergo oxidative phosphorylation (Zheng et al., 2016) and the signatures also include the unfolded protein response, but the influence of these ectopic pathways on neuronal maturation has not been examined in detail.”
BackgroundIntimate Relations—Mitochondria and Ageing
Webb, M., & Sideris, D. P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207580 · Cited by 36
“This is discussed in greater detail in Section 7 but here we note that stem cells are typically glycolytic with a low abundance of mitochondria [49] and several types of adult stem cell including neural and hematopoietic require a shift to OXPHOS in order to differentiate [50,51].”
BackgroundSignificance of mitochondrial activity in neurogenesis and neurodegenerative diseases
Sun, N., Ozgen, S., Krigman, J., & Zhang, R. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.322429 · Cited by 38
“Pyruvate kinase mRNA is altered via mRNA splicing, causing PKM2 to change to PKM1 (Zheng et al., 2016).”
BackgroundInfluentialAngelopoulos, I., Gakis, G., Birmpas, K., Kyrousi, C., Habeos, E. E., Kaplani, K., Lygerou, Z., Habeos, I. G., & Taraviras, S. L. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1009125 · Cited by 38
“In this figure the major changes in metabolic pathways occurring in quiescent and proliferating neural stem progenitor cells (NSPCs) as well as in immature neurons in the adult dentate gyrus and the developing forebrain are shown; FAO, Fatty Acid Oxidation; OXPHOS, Oxidative Phosphorylation; ROS, Reactive Oxygen Speci…”
BackgroundInfluentialPhotobiomodulation‐Induced Differentiation of Immortalized Adipose Stem Cells to Neuronal Cells
George, S., Hamblin, M. R., & Abrahamse, H. (2020) · Lasers in Surgery and Medicine · doi:10.1002/lsm.23265 · Cited by 33
“While pyruvate‐acetyl CoA maintains pluripotency in these cells, a progressive increase in the pyruvate‐lactate flux has been observed in Neural Progenitor Cells (NPCs) [22].”
BackgroundZielinski, J., Ducray, A., Moeller, A., Murbach, M., Kuster, N., & Mevissen, M. (2020) · Toxicology in Vitro · doi:10.1016/j.tiv.2020.104963 · Cited by 34
An NRF2 Perspective on Stem Cells and Ageing
Dodson, M. B., Anandhan, A., Zhang, D. D., & Madhavan, L. (2021) · Frontiers in Aging · doi:10.3389/fragi.2021.690686 · Cited by 35
Heiland, D. H., Gaebelein, A., Börries, M., Wörner, J., Pompe, N., Franco, P., Heynckes, S., Bartholomae, M., hAilín, D. Ó., Carro, M. S., et al. (2018) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0680 · Cited by 34
“other major brain functions (21), highlighting its potential impact in pathologic conditions.”
BackgroundHan, S., He, Z., Hu, X., Li, X., Zheng, K., Huang, Y., Xiao, P., Xie, Q., Ni, J., & Liu, Q. (2023) · Antioxidants · doi:10.3390/antiox12030722 · Cited by 34
“demonstrated that the metabolic pattern of neurons changes from OxPhos to aerobic glycolysis in the AD brain [25,56,57].”
BackgroundNeuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity
Yu, S. B., Wang, H., Sánchez, R. G., Carlson, N. M., Nguyen, K. Q., Zhang, A. J., Papich, Z. D., Abushawish, A. A., Whiddon, Z. D., Matysik, W., et al. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.05.008 · Cited by 31
Metabo-Devo: A metabolic perspective of development
Gándara, L., & Wappner, P. (2018) · Mechanisms of Development · doi:10.1016/j.mod.2018.02.004 · Cited by 31
Impact of Metabolic Pathways and Epigenetics on Neural Stem Cells
Fawal, M.-A., & Davy, A. (2018) · Epigenetics Insights · doi:10.1177/2516865718820946 · Cited by 31
Engel, D. F., Grzyb, A. N., de Oliveira, J., Pötzsch, A., Walker, T. L., Brocardo, P. S., Kempermann, G., & de Bem, A. F. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.09.002 · Cited by 33
Metabolic modulation regulates cardiac wall morphogenesis in zebrafish
Fukuda, R., Aharonov, A., Ong, Y. T., Stone, O. A., El-Brolosy, M. A., Maischein, H., Potente, M., Tzahor, E., & Stainier, D. Y. R. (2019) · eLife · doi:10.7554/elife.50161 · Cited by 32
“We found that upon CAERBB2 overexpression (OE), several glycolytic enzymes were upregulated, while mitochondrial proteins and oxidative phosphorylation (OXPHOS)-related enzymes were downregulated (Figure 2—source data 1).”
BackgroundInfluentialFaustman, D. L. (2020) · Journal of Internal Medicine · doi:10.1111/joim.13050 · Cited by 33
Metadata
- Authors
- Zheng, X., Boyer, L., Jin, M., Mertens, J., Kim, Y., Ma, L., Ma, L., Hamm, M., Gage, F. H., & Hunter, T.
- Affiliations
- Salk Institute for Biological Studies (US)
- Laboratory of Genetics, Salk Institute, La Jolla, United States
- Corresponding author
- Gage, Fred H
- Hunter, Tony
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-06-10
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4963198
- OpenAlex
- W2416068580
- Semantic Scholar
- fbed50febe18cd07bb8e0c7a00e748286b5070dc
- Cited by
- 671
- References
- 77
- Citations by year
- 2026: 82 · 2025: 76 · 2024: 84 · 2023: 81 · 2022: 74 · 2021: 85 · 2020: 65 · 2019: 49 · 2018: 39 · 2017: 33 · 2016: 1
- FWCI
- 20.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- California Institute for Regenerative Medicine (TR2-01778)
- Salk Pioneer postdoctoral fellowship
- The G. Harold and Leila Y. Mathers Foundation
- JPB Foundation
- Leona M. and Harry B. Helmsley Charitable Trust (#2012-PG-MED002)
- National Institutes of Health (CA14195, CA80100, CA82683)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- metabolic reprogramming, neuronal differentiation, aerobic glycolysis, oxidative phosphorylation, hexokinase 2, LDHA, c-Myc, MYCN, PGC-1α, estrogen-related receptor gamma, mitochondrial biogenesis, neural progenitor cells, neuronal cell death, mitochondrial mass
- MeSH terms
- Aerobiosis, Cell Differentiation, Cells, Cultured, Glycolysis, Humans, Metabolism, Oxidative Phosphorylation, Gene Expression Regulation, Developmental, Neural Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
