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Cited by 148Mitochondrial Function and PathologyAdipose Tissue and MetabolismMetabolism, Diabetes, and Cancer

Mitochondrial response to nutrient availability and its role in metabolic disease

Open access
Gao, Arwen W, Cantó, Carles, Houtkooper, Riekelt H·2014·EMBO Molecular Medicine
DOI 10.1002/emmm.201303782PMC PMC4023882
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Abstract

Metabolic inflexibility is defined as an impaired capacity to switch between different energy substrates and is a hallmark of insulin resistance and type 2 diabetes mellitus (T2DM). Hence, understanding the mechanisms underlying proper metabolic flexibility is key to prevent the development of metabolic disease and physiological deterioration. An important downstream player in the effects of metabolic flexibility is the mitochondrion. The objective of this review was to describe how mitochondrial metabolism adapts to limited nutrient situations or caloric excess by changes in mitochondrial function or biogenesis, as well as to define the mechanisms propelling these changes. Altogether, this should pinpoint key regulatory points by which metabolic flexibility might be ameliorated in situations of metabolic disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that metabolic flexibility—the ability to switch fuel oxidation to match fuel availability—depends on mitochondrial adaptation, and that metabolic disease reflects an impaired ability to adapt mitochondrial activity and biogenesis rather than simply reduced mitochondrial content. It integrates evidence on acute (dynamics, post-translational) and transcriptional (AMPK/SIRT1/PGC-1α, PPARs, SIRT3) control of mitochondrial metabolism under nutrient scarcity and caloric excess.

Key findings

  • Metabolic inflexibility is observable already in pre-diabetic insulin-resistant individuals, and mitochondrial number, structure, and function vary between insulin-resistant and insulin-sensitive subjects, suggesting mitochondrial dysfunction may contribute to insulin resistance.
  • Evidence for a causal role is conflicting: some mouse models overexpressing mitochondrial biogenesis proteins are insulin resistant, some models of mitochondrial dysfunction show increased insulin-stimulated glucose sensitivity, and T2DM patients have ~30% lower mitochondrial content yet higher mitochondrial oxidation rates and no intrinsic defect in increasing whole-body fat oxidation during exercise.
  • Nutrient scarcity promotes mitochondrial elongation via cAMP/PKA phosphorylation of Drp1 (blocking fission), while lipid overload induces fission and uncoupling; fasting also induces SIRT3, which deacetylates targets including NDUFA9, SOD2, LCAD, and OPA1.
  • Transcriptional control runs through AMPK (activated by rising AMP/ATP) phosphorylating PGC-1α and FOXO, priming them for SIRT1 deacetylation; caloric excess reduces SIRT1 and NAD+, raises GCN5 and NCoR1, and hyperacetylates/inactivates PGC-1α. One week of HFD raised SIRT3 and prevented hyperacetylation, but prolonged HFD decreased SIRT3 and produced hyperacetylation and mitochondrial dysfunction.

Methods

  • Narrative review integrating published literature on mitochondrial response to nutrient availability, structured around three questions: evidence for mitochondrial dysfunction in acquired metabolic disorders, how energy stress affects mitochondrial function (biogenesis, dynamics, mitophagy), and whether mitochondrial function is a realistic intervention target.
  • Covers acute mechanisms (fusion/fission proteins Mfn1, Mfn2, Opa1, Drp1, Mff, Fis1; acetylation/succinylation/malonylation) and transcriptional mechanisms (PPARs, PGC-1α, SIRT1, SIRT3, AMPK, FOXO, NCoR1), under both nutrient scarcity (fasting, caloric restriction) and caloric excess (high-fat feeding, obesity).
  • No primary data, systematic search strategy, or meta-analysis is reported.

Limitations

  • Stated: the causal link between mitochondrial function and metabolic disorders remains a challenge; it is unclear why mitochondrial content declines after prolonged fat overfeeding and how this can be prevented; whether insulin-sensitizing strategies can succeed without proper mitochondrial fitness is unresolved; the mechanism by which fission enhances uncoupling requires further study; the threshold and reason for long-term loss of protection are unsolved.
  • Evident from the text: as a narrative review it relies on cited studies of varying designs and species (mouse models, cell lines, human biopsies) without systematic quality appraisal; several proposed mechanisms (e.g., SIRT3 regulation, dexamethasone/Drp1 effects in other tissues, physiological role of succinylation and malonylation) are explicitly described as not yet understood or largely unexplored.

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Integrity signals

Registry

Crossref · 10.1002/emmm.201303782

Cites

86 of 86 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 112 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Mitochondrial dysfunction is at the center of many metabolic disorders, such as obesity and type 2 diabetes mellitus.

    “Mitochondrial dysfunction is at the center of many metabolic disorders, such as obesity and type 2 diabetes mellitus (T2DM) (Andreux et al, 2013).”
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  • Premisecitation

    Diverse mitochondrial parameters, such as mitochondrial number, structure, and function, vary between insulin-resistant and insulin-sensitive subjects.

    “Diverse mitochondrial parameters vary between insulin-resistant and insulin-sensitive subjects, such as mitochondrial number, structure, and function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Galgani et al, 2008 source

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  • Premisecitation

    Metabolic inflexibility can already be observed in pre-diabetic individuals suffering from insulin resistance.

    “Interestingly, metabolic inflexibility can already be observed in pre-diabetic individuals suffering from insulin resistance (Corpeleijn et al, 2009), limiting the ability to switch from fatty acid breakdown to fat storage after a meal and vice versa (Kelley, 2005).”
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  • Premisecitation

    Metabolically inflexible individuals fail to adapt their fuel preference to changes in carbohydrate or lipid supplies.

    “In turn, metabolically inflexible individuals fail to adapt their fuel preference to changes in carbohydrate or lipid supplies (Galgani et al, 2008).”
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  • Premisecitation

    Metabolic inflexibility is a hallmark of insulin resistance and type 2 diabetes mellitus.

    “Metabolic inflexibility is defined as an impaired capacity to switch between different energy substrates and is a hallmark of insulin resistance and type 2 diabetes mellitus (T2DM).”
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    • cites Galgani et al, 2008 source

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  • Classified as probably not a substantial claim. 7

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    Interpretationreasoning

    Some tissues, such as human muscle, might have a notable reserve of respiratory capacity, and minor changes in their mitochondrial content might not be enough to limit resting respiratory needs.

    “This highlights how some tissues, such as human muscle, might actually have a notable reserve of respiratory capacity, and that minor changes in their mitochondrial content might not be enough to limit resting respiratory needs.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The decreased mitochondrial content in insulin-resistant old individuals seems to be linked to decreased physical activity and can be enhanced in response to exercise.

    “Similarly, the decreased mitochondrial content in insulin-resistant old individuals seems to be rather linked to decreased physical activity and can be perfectly enhanced in response to exercise (Broskey et al, 2014).”
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    Premisecitation

    PPARβ/δ triggers fatty acid β-oxidation in muscle and adipose tissue, which results in enhanced fat breakdown.

    “PPARβ/δ triggers fatty acid β-oxidation in muscle and adipose tissue, which results in enhanced fat breakdown (Wang et al, 2003; Varga et al, 2011).”
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    Premisecitation

    Type 2 diabetes mellitus patients, despite having a 30% lower mitochondrial content, have higher mitochondrial oxidation rates and do not have an intrinsic problem to increase their whole-body fat oxidation rate during exercise.

    “Finally, T2DM patients, despite having a 30% lower mitochondrial content, have higher mitochondrial oxidation rates and do not have an intrinsic problem to increase their whole-body fat oxidation rate during exercise (Larsen et al, 2009; Holloszy, 2013).”
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    Premisecitation

    Intramyocellular lipid levels were increased in first-level relatives of type 2 diabetes mellitus patients and were associated with impaired insulin-stimulated glucose uptake in muscle.

    “For instance, IMCL levels were increased in first-level relatives of T2DM patients and associated with impaired insulin-stimulated glucose uptake in muscle (Pan et al, 1997).”
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    Premisecitation

    PPARs are nuclear receptors that directly bind specific lipid species that generally increase upon cellular fat overflow and control different transcriptional programs linked to lipid metabolism.

    “PPARs are nuclear receptors that directly bind specific lipid species that generally increase upon cellular fat overflow in the cells. There are three PPARs: α, β (also known as δ) and γ. Each of these binds specific lipid species as ligands and controls different transcriptional programs linked to lipid metabolism (Wahli & Michalik, 2012).”
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    Premisecitation

    Lipids interfere with insulin signaling and represent one of the key aspects that could contribute to insulin resistance in situations of high-fat feeding or lipid infusion.

    “These lipids interfere with insulin signaling and represent one of the key aspects that could contribute to insulin resistance in situations of high-fat feeding or lipid infusion (Pan et al, 1997; Krssak et al, 1999; Goodpaster et al, 2000).”
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    Premisecitation

    Mitochondrial dysfunction is observed only after prolonged high-fat feeding, while insulin resistance develops earlier.

    “Also, mitochondrial dysfunction is observed only after prolonged high-fat feeding, while insulin resistance develops earlier (Hancock et al, 2008).”
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    Premisecitation

    Cells under a well-fed condition maintain their mitochondria in a separated or fragmented state, while under fasting or starved conditions mitochondria tend to persist in a connected or fused state.

    “Cells under a well-fed condition maintain their mitochondria in a separated (or fragmented) state, while under fasting or starved conditions, mitochondria tend to persist in a connected (or fused) state (Gomes et al, 2011).”
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    Interpretationnone given

    Mitochondrial activity can be controlled through at least two major mechanisms: acute mechanisms that qualitatively modify mitochondrial function and longer-term transcriptional mechanisms that increase mitochondrial number.

    “Mitochondrial activity can be controlled through at least two major mechanisms: acute ones, aimed to qualitatively modify mitochondrial function, and longer-term transcriptional mechanisms, aimed to increase mitochondrial number.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Initial evidence indicated that caloric restriction enhances mitochondrial content.

    “Initial evidence indicated that CR enhances mitochondrial content (Nisoli et al, 2005).”
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    Premisecitation

    Increased SIRT3 activity facilitates optimal fatty acid oxidation, mitochondrial electron transfer, and protection against reactive oxygen species.

    “The increased SIRT3 activity facilitates optimal fatty acid oxidation, mitochondrial electron transfer and protection against reactive oxygen special all at once (He et al, 2012).”
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    Premisecitation

    A recent report indicates that caloric restriction enhances mitochondrial function without changes in mitochondrial content or biogenesis.

    “Interestingly, a recent report indicates that CR enhances mitochondrial function without changes in mitochondrial content or biogenesis (Lanza et al, 2012).”
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    Premisecitation

    Dexamethasone induces Drp1 expression in liver cells and thereby changes mitochondrial morphology and metabolism that favor gluconeogenic procedures.

    “For example, dexamethasone induces Drp1 expression in liver cells and thereby changes mitochondrial morphology and metabolism that favor gluconeogenic procedures (Hernandez-Alvarez et al, 2013).”
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    Premisecitation

    Different situations of energy restriction, including fasting and exercise, increase NAD+ levels and trigger SIRT1/PGC-1α-dependent mitochondrial adaptation.

    “Indeed, different situations of energy restriction, including fasting and exercise, increase NAD+ levels and trigger SIRT1/PGC-1α-dependent mitochondrial adaptation (Lin et al, 2000; Houtkooper et al, 2012).”
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    Premisecitation

    Exogenously providing NAD+ precursors can enhance SIRT3 activity in mammalian cells and tissues and rescue deficient SIRT3 activity in a model for complex I deficiency.

    “Indeed, exogenously providing NAD+ precursors can enhance SIRT3 activity in mammalian cells and tissues (Canto et al, 2012) and rescue deficient SIRT3 activity in a model for complex I deficiency (Karamanlidis et al, 2013).”
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    Premisecitation

    Elongated mitochondria upon fasting possess more cristae and increased levels of dimerization and activity of ATP synthase, ensuring a better coupling of fuel oxidation with ATP synthesis.

    “Elongated mitochondria upon fasting possess more cristae and increased levels of dimerization and activity of ATP synthase, ensuring a better coupling of fuel oxidation with ATP synthesis (Gomes et al, 2011).”
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    Premisenone given

    In the basal state, PGC-1α is acetylated, which dampens PGC-1α activity.

    “In the basal state, PGC-1α is acetylated, which dampens PGC-1α activity.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The two-step activation of PGC-1α might be a conserved mechanism for AMPK to confer specificity among the various targets of SIRT1.

    “This two-step activation of PGC-1α might be a conserved mechanism for AMPK to confer specificity among the various targets of SIRT1 (Canto & Auwerx, 2010).”
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    Premisecitation

    Upon fasting, SIRT3 expression is rapidly induced and deacetylates key residues on mitochondrial proteins.

    “Upon fasting, SIRT3 expression is rapidly induced and deacetylates key residues on mitochondrial proteins (Hirschey et al, 2010).”
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    Interpretationreasoning

    SIRT3 regulates more accessible hydrophilic residues, while residues on hydrophobic regions are less accessible and prone to become acetylated.

    “This suggests that SIRT3 regulates more accessible hydrophilic residues, while residues on hydrophobic regions are less accessible and prone to become acetylated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Nutrient scarcity in organisms is linked to an increase in circulating glucagon and other stress hormones, such as norepinephrine, which generally increase intracellular cAMP levels and PKA signaling.

    “Nutrient scarcity in organisms is linked to an increase in circulating glucagon and other stress hormones, such as norepinephrine, which generally increase intracellular cAMP levels and PKA signaling (Fig 2A).”
    Quote in the paperSubstantial claim

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    Premisecitation

    PPARγ controls lipogenic and adipocyte differentiation gene expression and activates lipid storage.

    “In contrast, PPARγ controls lipogenic and adipocyte differentiation gene expression and activates lipid storage (Varga et al, 2011; Wahli & Michalik, 2012).”
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    Premisecitation

    FOXO transcription factors are effectors of AMPK and are also targets for deacetylation by SIRT1.

    “Other effectors of AMPK are the FOXO transcription factors (Greer et al, 2007), which are also a target for deacetylation by SIRT1 (Brunet et al, 2004).”
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    Premisecitation

    Upon nutrient stress, the NAD+-dependent deacetylase SIRT1 activates PGC-1α, a reaction that is rate-limited by availability of the metabolite NAD+.

    “Upon nutrient stress, the NAD+-dependent deacetylase SIRT1 activates PGC-1α, a reaction that is rate-limited by availability of the metabolite NAD+ (Houtkooper et al, 2010a).”
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    Premisenone given

    Upon activation, AMPK activates catabolic pathways and switches off energy-consuming processes.

    “Upon activation, AMPK activates catabolic pathways and switches off energy-consuming processes.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Mitochondrial function can dramatically change through fusion/fission or post-translational modifications of mitochondrial proteins.

    “While most studies observe mitochondria in a steady state, mitochondrial function can dramatically change through fusion/fission or post-translational modifications of mitochondrial proteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Reductions in the content of mitochondrial enzymes and alterations in mitochondrial shape were observed in muscles from patients with T2DM.

    “However, most of the data supporting this concept are based on the fact that reductions in the content of mitochondrial enzymes and alterations in mitochondrial shape were observed in the muscles from patients with T2DM.”
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  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Disruption of mitochondrial function leads to increases in basal and insulin-stimulated glucose uptake in some models.

    “disruption of mitochondrial function leads to increases in basal and insulin-stimulated glucose uptake in some models”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Higher mitochondrial content could also be due to deficiencies in mitochondrial recycling mechanisms and in fact be linked to mitochondrial dysfunction.

    “Indeed, higher mitochondrial content could also be due to deficiencies in mitochondrial recycling mechanisms and in fact be linked to mitochondrial dysfunction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    During HFD, SIRT1 expression is reduced, while GCN5 acetyltransferase, which acetylates PGC-1α, is expressed at higher levels.

    “During HFD, SIRT1 expression is reduced, while the GCN5 acetyltransferase, which acetylates PGC-1α, is expressed at higher levels (Coste et al, 2008).”
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    Premisenone given

    Accumulation of lipids could impair insulin signaling.

    “This went hand in hand with the accumulation of lipids that could impair insulin signaling.”
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    Premisecitation

    Prolonged HFD dramatically decreases SIRT3 expression, correlating with the appearance of mitochondrial hyperacetylation and mitochondrial dysfunction.

    “Conversely, prolonged HFD dramatically decreases SIRT3 expression, correlating with the appearance of mitochondrial hyperacetylation and mitochondrial dysfunction (Hirschey et al, 2010).”
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    Premisecitation

    One week of HFD enhanced SIRT3 levels and prevented mitochondrial hyperacetylation despite higher levels of lipid substrates.

    “One week of HFD enhanced SIRT3 levels and prevented mitochondrial hyperacetylation despite the higher levels of lipid substrates (Hirschey et al, 2010).”
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    Premisecitation

    Deletion of Mfn2 in the liver disrupts mitochondria-ER connectivity and thereby induces ER stress-mediated susceptibility to metabolic disease upon high-fat feeding.

    “Indeed, deletion of Mfn2 in the liver disrupts mitochondria-ER connectivity and thereby induces ER stress-mediated susceptibility to metabolic disease upon high-fat feeding (Sebastian et al, 2012), indicating once more that the regulation of mitochondrial dynamics is essential to meet metabolic challenges.”
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    Premisecitation

    Muscle-specific AMPK knockouts display enlarged but dysfunctional mitochondria.

    “This is the case, for example, in muscle-specific AMPK knockouts, which display enlarged but dysfunctional mitochondria (O'Neill et al, 2011).”
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    Premisecitation

    Expression of repressive transcriptional regulators, such as NCoR1, is enhanced by HFD, repressing genes that control mitochondrial activity and contributing to excessive calorie storage.

    “The expression of repressive transcriptional regulators, such as the nuclear receptor corepressor 1 (NCoR1), is also enhanced by HFD, repressing genes that control mitochondrial activity and contributing to the excessive calorie storage (Yamamoto et al, 2011) (Fig 3C).”
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    Premisereasoning

    Mfn2 expression is reduced, possibly through transcriptional regulation.

    “Still, however, Mfn2 expression is also reduced, possibly through transcriptional regulation.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In Zucker rats and obese humans, Mfn2 was strongly decreased in skeletal muscle tissues compared to controls, and this was associated with a smaller mitochondrial network and size.

    “Studies in Zucker rats and obese humans have shown that Mfn2 was strongly decreased in their skeletal muscle tissues compared to the control groups, which was associated with smaller mitochondrial network and size (Bach et al, 2003).”
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39 of 39

  • The paper relies on this without support.

    The influence of limited nutrient availability, such as fasting and caloric restriction, or excessive nutrient supply, such as high-fat feeding, on mitochondrial processes is only sparsely described.

    “However, it is only sparsely described how these processes are influenced by situations of limited nutrient availability, such as fasting and caloric restriction (CR), or by excessive nutrient supply, such as high-fat feeding.”

  • The paper relies on this without support.

    Compliance with regular exercise and restricted food intake is poor, and the metabolic syndrome epidemic is still spreading.

    “However, compliance is poor and the metabolic syndrome epidemic is still spreading.”

  • The paper relies on this without support.

    The relationship between caloric restriction and mitochondrial regulation is still under debate.

    “The relationship between CR and mitochondrial regulation is, however, still under debate.”

  • The paper relies on this without support.

    The mechanisms underlying the enhanced mitochondrial function induced by caloric restriction are not clear.

    “The mechanisms underlying this enhanced function are, however, not clear.”
4 of 4

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Each contradiction between two passages listed here was confirmed by an independent check.

  • Drp1 oligomerization is described as required for fusion

    Minor

    The text says fusion during energy stress requires mitochondrial oligomerization of Drp1, but immediately says preventing Drp1 from docking on mitochondria prevents fission and favors fusion.

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Authors
Gao, A. W., Cantó, C., & Houtkooper, R. H.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Nestlé (Switzerland) (CH)
Corresponding author
Houtkooper, Riekelt H
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2014-03-12
Volume
6
Issue
5
Pages
580-589
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.1002/emmm.201303782
PMC
PMC4023882
OpenAlex
W2155904682
Semantic Scholar
0d0ed25b1ed5d47aa2cec8e11df373e823c0fae4
Cited by
148
References
85
Citations by year
2026: 5 · 2025: 11 · 2024: 11 · 2023: 8 · 2022: 10 · 2021: 12 · 2020: 18 · 2019: 10 · 2018: 15 · 2017: 14 · 2016: 19 · 2015: 13 · 2014: 2
FWCI
1.48
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Funders
ZonMw‐VENI (91613050)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
mitochondrial metabolism, metabolic flexibility, nutrient availability, mitochondrial biogenesis, insulin resistance, type 2 diabetes, caloric excess, metabolic disorders
MeSH terms
Adaptation, Physiological, Food, Humans, Metabolic Diseases, Mitochondria

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