Cited by 671Neurogenesis and neuroplasticity mechanismsCancer, Hypoxia, and MetabolismMetabolism, Diabetes, and Cancer

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 access

Zheng, Xinde, Boyer, Leah, Jin, Mingji, Mertens, Jerome, Kim, Yongsung, Ma, Li, Ma, Li, Hamm, Michael, Gage, Fred H, Hunter, Tony·2016·eLife

DOI 10.7554/elife.13374PMC PMC4963198

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Abstract

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.

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

Crossref · 10.7554/elife.13374

Cites

77 of 77 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

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
“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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
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 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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes

Show all 99 claims

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
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Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably 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
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
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
“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
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
- Rests on an assumption: Neurons rely on oxidative phosphorylation to meet energy demands.
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
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It 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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably 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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
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
- Not checked yetcites Suzuki et al., 2011 source
- Not checked yetcites Lee et al., 2012 source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It 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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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 calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

56 of 56

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”

7 of 7

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?

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
Minor
The results say the HK2 and LDHA knockdown experiment used passage-3 NPCs, while the Figure 3C caption says passage 2.
Figure 1 caption reverses the TCA and PDH panel assignments
Minor
In 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.

2 of 2

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).”
BackgroundMethod
Understanding 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).”
Background
Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation
Trapnell, 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
Integrative genomics viewer
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).”
MethodInfluential
Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks
Trapnell, 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).”
Method
Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455
An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex
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).”
Result
Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1
Wu, 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).”
Background
Chronic 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).”
Background
Hypoxia-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

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Influential
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Self-citation

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
ORCID: Zheng, Xinde
Boyer, Leah
Kim, Yongsung
Gage, Fred H
Hunter, Tony
Venue: eLife
Publisher: eLife Sciences Publications, Ltd
Published: 2016-06-10
Volume: 5
ISSN: 2050-084X (ISSN-L)
DOI: 10.7554/elife.13374
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: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
creativecommons.org/licenses/by/4.0/ (am)
creativecommons.org/licenses/by/4.0/ (tdm)
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

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Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation

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