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Cited by 344Metabolism, Diabetes, and CancerMitochondrial Function and PathologyAdipose Tissue and Metabolism

Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle

Open access
Muoio, Deborah M., Neufer, P. Darrell·2012·Cell Metabolism
DOI 10.1016/j.cmet.2012.04.010PMC PMC3348508
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Abstract

The interplay between mitochondrial energetics, lipid balance, and muscle insulin sensitivity has remained a topic of intense interest and debate for decades. One popular view suggests that increased oxidative capacity benefits metabolic wellness, based on the premise that it is healthier to burn fat than glucose. Attempts to test this hypothesis using genetically modified mouse models have produced contradictory results and instead link muscle insulin resistance to excessive fat oxidation, acylcarnitine production, and increased mitochondrial H(2)O(2)-emitting potential. Here, we consider emerging evidence that insulin action in muscle is driven principally by mitochondrial load and redox signaling rather than oxidative capacity.

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Crossref · 10.1016/j.cmet.2012.04.010

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Claims the paper makes

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  • Premisecitation

    The same allosteric effectors activate pyruvate dehydrogenase kinases, which phosphorylate pyruvate dehydrogenase and further inhibit its catalytic activity.

    “This same set of allosteric effectors activates a family of pyruvate dehydrogenase kinases that phosphorylate PDH, further inhibiting the catalytic activity of the enzyme (Sugden and Holness, 2006).”
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    Intramyocellular lipid content is a strong predictor of insulin resistance.

    “Subsequent studies identified intramyocellular lipid content as a strong predictor of insulin resistance.”
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    A caveat of these and similar animal studies is that their methods did not account for label dilution from hydrolysis and catabolism of endogenous lipids, which are more abundant in obesity.

    “A notable caveat of these and several similar animal studies is that the methods used did not account for potential label dilution effects due to hydrolysis and catabolism of endogenously-derived lipids, which are more abundant in the obese state (Boyle et al., 2011; Thyfault et al., 2010).”
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    Intramuscular and/or hepatic content of triacylglycerol, diacylglycerol, and/or ceramide correlates negatively with insulin sensitivity.

    “Support for this model grew from numerous reports showing that intramuscular and/or hepatic content of triacylglycerol, diacylglycerol and/or ceramide correlate negatively with insulin sensitivity (Erion and Shulman, 2010; Goodpaster and Kelley, 2002; Holland and Summers, 2008).”
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    The negative relationship between lipid content and insulin sensitivity is evident in obese and diabetic humans and in several rodent and cell culture models of metabolic disease and/or chronic lipid exposure.

    “This relationship is evident in obese and diabetic humans as well as in several rodent and cell culture models of metabolic disease and/or chronic lipid exposure (An et al., 2004; Hulver et al., 2003; Nagle et al., 2009).”
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    Premisecitation

    The glucose-fatty acid cycle model proposes that increased fatty acid supply and oxidation cause cellular accumulation of acetyl-CoA, NADH, and ATP, which allosterically inhibit pyruvate dehydrogenase.

    “The model was developed based on the finding that increasing the supply and oxidation of fatty acids leads to cellular accumulation of acetyl-CoA, NADH and ATP, which allosterically inhibit pyruvate dehydrogenase (PDH), the mitochondrial enzyme complex that couples glycolysis to glucose oxidation.”
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    • cites Randle et al., 1963 source

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    Interpretationnone given

    Tests of whether greater oxidative capacity improves metabolic health in genetically modified mice have given conflicting results and instead associate muscle insulin resistance with excessive fat oxidation, acylcarnitine production, and higher mitochondrial H2O2 emission potential.

    “Attempts to test this hypothesis using genetically-modified mouse models have produced contradictory results; and instead link muscle insulin resistance to excessive fat oxidation, acylcarnitine production and increased mitochondrial H2O2 emitting potential.”
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    Premisecitation

    Human studies suggest that skeletal muscle fat oxidation capacity is lower in obese than lean subjects, with mitochondrial insufficiencies most pronounced in severe obesity and/or diabetes.

    “Human studies that measured whole body substrate selection by indirect calorimetry, fatty acid flux across the leg, fatty acid oxidation in isolated skeletal muscle strips and/or maximal activities of various oxidative enzymes in biopsy specimens, strongly suggested that skeletal muscle capacity to oxidize fat is lower in obese compared to lean subjects; with the apparent mitochondrial insufficien”
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    Premisecitation

    Randle proposed that a rise in cellular citrate inhibits phosphofructokinase-1, and that reduced glycolysis and pyruvate oxidation cause glucose-6-phosphate accumulation, allosteric hexokinase inhibition, and diminished glucose uptake.

    “Randle further proposed that a rise in cellular citrate would inhibit phosphofructokinase-1 (Denton and Randle, 1966), and that lowering of glycolysis and pyruvate oxidation would result in accumulation of glucose-6-phosphate, leading to allosteric inhibition of hexokinase and thus diminished glucose uptake.”
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    Premisereasoning

    Lipid-induced insulin resistance is not due to inhibition of glycolysis and glucose oxidation but instead stems from accumulation of lipid signaling molecules such as diacylglycerol and ceramide that disrupt insulin-stimulated GLUT4 translocation.

    “Together, these observations led to the conclusion that lipid-induced insulin resistance is not due to inhibition of glycolysis and glucose oxidation, but instead stems from a more direct and proximal mechanism wherein tissue accumulation of lipid signaling molecules such as diacylglycerol and ceramide disrupt insulin-stimulated translocation of the GLUT4 glucose transporter.”
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    Interpretationcitation

    These findings suggest that during diet-induced obesity/diabetes etiology, mitochondrial architecture deteriorates, ultimately leading to mitophagy and complete organelle dissolution.

    “These findings suggest that at some point in the etiology of diet-induced obesity/diabetes, mitochondrial architecture begins to deteriorate, ultimately leading to mitophagy and the complete dissolution of the organelle (Mitsuhashi et al., 2011).”
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    Interpretationreasoning

    Lower resting substrate flux and/or ATP synthesis should not be interpreted as mitochondrial dysfunction or blamed for local lipid metabolite accumulation.

    “Lower rates of substrate flux and/or ATP synthesis measured at rest should not be interpreted as evidence of mitochondrial dysfunction nor blamed for local accumulation of lipid metabolites.”
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    • Rests on an assumption: Mitochondrial respiration in all cells is governed by energy demand, including basal or idling respiratory activity and ATP regeneration.

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    Premisecitation

    Skeletal muscle from obese humans with or without diabetes has reduced overall mitochondrial content and morphological changes similar to animal models.

    “Skeletal muscle from obese humans with or without diabetes is characterized by reduced overall mitochondrial content with evidence of morphological changes similar to those in the animal models (Chomentowski et al., 2011; Kelley et al., 2002; Ritov et al., 2005).”
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    Interpretationnone given

    Without a corresponding reduction in caloric intake, the probability that fuel supply exceeds demand increases, not because oxidative capacity is diminished but because the costs of maintaining energy balance decrease.

    “Without a corresponding reduction in caloric intake, the probability that fuel supply will exceed demand increases, not because of diminished oxidative capacity but because the costs of maintaining energy balance decrease.”
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    Premisecitation

    Magnetic resonance spectroscopy studies found mitochondrial substrate flux and/or ATP synthesis rates depressed in muscle of elderly insulin-resistant individuals and lean insulin-resistant young subjects with a family history of type 2 diabetes.

    “Additional investigations employing non-invasive magnetic resonance spectroscopy (MRS) found that both mitochondrial substrate flux and/or ATP synthesis rates were depressed in muscle of elderly individuals with insulin resistance (Petersen et al., 2003) and in lean, insulin-resistant young subjects with a family history of type 2 diabetes (Petersen et al., 2004).”
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    Premisecitation

    These studies led to the proposal that insulin-resistant humans have faulty muscle mitochondria and intrinsic oxidative metabolism deficiencies that divert fatty acids from oxidation toward diacylglycerols and other toxic lipids, impairing insulin signaling.

    “These and other studies led to the proposal that insulin resistant humans have faulty muscle mitochondria and intrinsic deficiencies in oxidative metabolism that impinge on insulin signaling by diverting fatty acids away from oxidation and toward production of diacylglycerols and other toxic lipid species (Lowell and Shulman, 2005; Roden, 2005).”
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    Transgenic mouse models with targeted disruptions in mitochondrial proteins or master regulators of mitochondrial biogenesis have severely compromised oxidative performance, but many show increased insulin sensitivity relative to wild type, even on a fat-enriched diet.

    “As anticipated these mice have severely compromised oxidative performance, but contrary to the predicted development of insulin resistance, many of these transgenic models display increased insulin sensitivity relative to wild type mice, even when challenged with a fat-enriched diet (reviewed in (Muoio, 2010)).”
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    Premisecitation

    In second-generation ACC2 knockout models, the switch to fat catabolism was offset by diminished glucose oxidation and a reciprocal rise in de novo lipogenesis.

    “Instead, the genetically engineered switch to fat catabolism was offset by diminished glucose oxidation and a reciprocal rise in de novo lipogenesis.”
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    Premisecitation

    Early stages of diet-induced insulin resistance are characterized by increasing β-oxidation and no change in respiratory capacity.

    “In aggregate, the results showed that the early stages of diet-induced insulin resistance are characterized by increasing β-oxidation and no change in respiratory capacity (Hancock et al., 2008; Kraegen et al., 2008; Noland et al., 2009).”
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    ACC2−/− mice have higher whole-body and muscle fatty acid oxidation rates.

    “Indeed, ACC2−/− mice proved to have higher whole-body and muscle fatty acid oxidation rates (Abu-Elheiga et al., 2001; Abu-Elheiga et al., 2003).”
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    In ACC2−/− mice, both fat and carbohydrate oxidation are simultaneously increased, which was credited as the impetus for increased total body energy expenditure without considering changes in energy demand.

    “Both fat and carbohydrate oxidation were simultaneously increased in ACC2−/− mice, which was curiously credited as the impetus for increased total body energy expenditure without consideration of potential changes in energy demand (Choi et al., 2007).”
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    ACC2 is localized on the outer mitochondrial membrane and catalyzes malonyl-CoA synthesis, which inhibits CPT-1, the gatekeeper for fatty acid entry into mitochondria.

    “ACC2 appears to be localized on the outer mitochondrial membrane (Abu-Elheiga et al., 2001) where it catalyzes the synthesis of malonyl-CoA, a potent inhibitor of carnitine palmitoyltransferase-1 (CPT-1); the enzyme that functions as the gatekeeper for fatty acid entry into the mitochondria.”
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    Two other groups generated whole-body and muscle-specific ACC2 knockout models and found no effect of gene deletion on body weight, food intake, body composition, or susceptibility to diet-induced obesity and glucose intolerance.

    “Intriguingly however, two other groups have recently generated whole body- and muscle-specific ACC2 knockout models and found no effect of the gene deletion on body weight, food intake, body composition and susceptibility to diet-induced obesity and glucose intolerance (Hoehn et al., 2010; Olson et al., 2010).”
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    Premisecitation

    Diet-induced and genetic insulin resistance are associated with high rates of incomplete fat oxidation, shown by intramuscular accumulation of mitochondrial-derived fatty acylcarnitine intermediates and reduced TCA cycle intermediates.

    “This situation first came to light with the discovery that both diet-induced and genetic forms of insulin resistance were associated with high rates of incomplete fat oxidation, evidenced by intramuscular accumulation of several mitochondrial-derived fatty acylcarnitine intermediates and reduced levels of TCA cycle intermediates (Koves et al., 2005; Koves et al., 2008).”
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    Premisecitation

    ACC2−/− mice are hyperphagic but maintain normal body weight, glycemic control, and muscle insulin sensitivity even on a high fat diet.

    “These animals were also hyperphagic but maintained normal body weight, glycemic control and muscle insulin sensitivity, even when fed a high fat diet (Abu-Elheiga et al., 2003; Choi et al., 2007).”
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    Premisecitation

    PPARs are lipid-activated nuclear receptors that stimulate expression of genes involved in fatty acid transport and oxidation.

    “Another approach that is commonly deployed to evaluate the role of mitochondrial fatty acid oxidation in the etiology of insulin resistance centers on exploitation of the peroxisome proliferator-activated receptors (PPAR α, β/δ and ), a family of lipid-activated nuclear receptors that stimulate expression of genes involved in transport and oxidation of fatty acids (Desvergne et al., 1998).”
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    Premisecitation

    In type 2 diabetic humans and obese rodents, oral CPT-1 inhibitors such as etomoxir and oxfenicine consistently elevate glucose oxidation and ameliorate hyperglycemia and hyperinsulinemia.

    “In type 2 diabetic humans and in obese rodents, oral administration of CPT-1 inhibitors such as etomoxir and oxfenicine consistently elevates glucose oxidation and ameliorates hyperglycemia and hyperinsulinemia (Barnett et al., 1992; Deems et al., 1998; Dobbins et al., 2001; Fragasso et al., 2009; Hubinger et al., 1997).”
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    Premisecitation

    Massive overexpression of any mitochondrial membrane protein tends to disrupt native stoichiometry and mitochondrial membrane integrity, producing artifactual acceleration in proton conductance and increased energy expenditure.

    “Moreover, massive overexpression of any mitochondrial membrane protein tends to disrupt the native stoichiometry and integrity of the mitochondrial membrane, generating an artifactual acceleration in proton conductance and a concomitant increase in energy expenditure (Cadenas et al., 2002; Harper et al., 2002; Henique et al., 2010; Perdomo et al., 2004; Sebastian et al., 2007)”
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    Interpretationreasoning

    The genetic approaches used in CPT-1 overexpression studies yield poor transfection efficiencies, raising the question of whether enhanced insulin action in the whole myocyte/myofiber population was due to events within transfected cells.

    “Notably however, the genetic approaches used in these studies yield notoriously poor transfection efficiencies, thereby raising the question of whether enhanced insulin action measured in the entire population of myocytes/myofibers was actually due to events occurring within the transfected cells.”
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    • Rests on an assumption: The genetic approaches used in CPT-1 overexpression studies yield notoriously poor transfection efficiencies.

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    Premisecitation

    Chronic etomoxir administration causes severe hepatic steatosis and heightened oxidative stress.

    “Interpretation of these studies is further complicated by the observation that chronic administration of etoxomir causes severe hepatic steatosis, while also provoking a state of heightened oxidative stress (Vickers et al., 2006).”
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    Interpretationcitation

    Potent inhibition of liver CPT-1 leads to undesirable outcomes, while the potential utility of specifically inhibiting skeletal muscle CPT-1 remains unclear.

    “Thus, potent inhibition of liver CPT-1 clearly leads to undesirable outcomes, whereas the potential utility of specifically inhibiting skeletal muscle CPT-1 remains unclear.”
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    Premisecitation

    Metabolic inflexibility was first introduced in a report showing healthy individuals shift from robust fat oxidation in the fasted state to high glucose oxidation during a hyperinsulinemic-euglycemic clamp, whereas obese and type 2 diabetic subjects show little response.

    “This phenomenon, commonly known as “metabolic inflexibility”, was first introduced in a report showing that healthy individuals shift from robust fat oxidation in the fasted state to a high rate of glucose oxidation in response to a hyperinsulinemic-euglycemic clamp (measured by whole body or leg RQ), whereas obese and type 2 diabetic subjects showed little response (Kelley et al., 1999).”
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    Premisecitation

    Treating mice with PPARα or PPARβ/δ agonists increases whole-body oxygen consumption without affecting caloric intake, accounting for lower weight gain during high fat feeding.

    “Treating mice with PPARα or PPARβ/δ agonists also induces, either directly or indirectly, an increase in whole body oxygen consumption without affecting caloric intake, thus accounting for lower rates of weight gain in response to high fat feeding (Guerre-Millo et al., 2000; Tanaka et al., 2003).”
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    Premisecitation

    Mice lacking PDH kinase 4 have elevated PDH activity and enhanced glucose tolerance.

    “The notion that pyruvate trafficking can indeed impact systemic glucose homeostasis is strengthened by studies in mice lacking PDH kinase 4, which have elevated PDH activity and enhanced glucose tolerance (Jeoung and Harris, 2008).”
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    Interpretationcitation

    PPARα overexpression creates a situation where forced flux through β-oxidation outpaces respiratory demand, and added reducing pressure from high rates of incomplete oxidation interferes with insulin action.

    “This implies that PPARα overexpression creates a situation wherein forced flux through β-oxidation outpaces the demand of the respiratory system, and that the added reducing pressure imposed by high rates of incomplete oxidation interferes with insulin action.”
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    Premisecitation

    Lowering mitochondrial acyl-CoAs, resulting in increased PDH activity and improved metabolic flexibility, can be achieved via dietary L-carnitine supplementation.

    “Moreover, recent evidence suggests that lowering of mitochondrial acyl CoAs, resulting in increased PDH activity and improved metabolic flexibility, can be achieved via dietary supplementation with L-carnitine (Noland et al., 2009; Power et al., 2007).”
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    Interpretationreasoning

    CrAT opposes the Randle cycle by permitting mitochondrial efflux of excess carbons, thereby facilitating an efficient transition from fat to glucose during the fasted-to-fed transition.

    “These results suggest that CrAT opposes the Randle cycle by permitting mitochondrial efflux of excess carbons, which thereby facilitates an efficient transition from fat to glucose during the fasted to fed transition.”
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    Premisecitation

    In rodents fed a high-fat diet, limitations to muscle glucose uptake reside at the levels of glucose delivery and phosphorylation, as well as GLUT4 transport.

    “experiments employing a counter-transport technique concluded that limitations to muscle glucose uptake in rodents fed a high fat diet reside at the levels of glucose delivery and phosphorylation, as well as GLUT4 transport (Wasserman, 2009).”
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    Premisecitation

    TXNIP antagonizes glucose uptake through a yet undefined mechanism.

    “TXNIP not only binds to and inhibits thioredoxin, but also antagonizes glucose uptake through a yet undefined mechanism (Parikh et al., 2007).”
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    Premisecitation

    Mitochondrial-derived ROS modulate insulin signaling.

    “mitochondrial-derived ROS modulate insulin signaling (Bloch-Damti and Bashan, 2005; Evans et al., 2005).”
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    Premisecitation

    Hexokinases I and II can translocate to the mitochondrial outer membrane, where their catalytic activities are less sensitive to product inhibition.

    “hexokinases I and II can translocate to the mitochondrial outer membrane where their catalytic activities are less sensitive to product inhibition (Azoulay-Zohar et al., 2004; Hashimoto and Wilson, 2002; John et al., 2011).”
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    Premisecitation

    Muscle-specific ablation of CrAT results in blunted switching from fatty acid to glucose substrate at the whole-body level and in isolated mitochondria.

    “blunted switching from fatty acid to glucose substrate at the whole body level and in isolated mitochondria”
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    • cites Muoio et al., (in press)

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    Premisecitation

    TXNIP is a redox-regulatory protein belonging to the α-arrestin family.

    “thioredoxin interacting protein (TXNIP), a redox-regulatory protein belonging to the α-arrestin family (Chutkow et al., 2010; Hui et al., 2008).”
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    Premisecitation

    TXNIP binds to and inhibits thioredoxin.

    “TXNIP not only binds to and inhibits thioredoxin, but also antagonizes glucose uptake through a yet undefined mechanism (Parikh et al., 2007).”
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    Interpretationreasoning

    Competition between oxidative substrates might increase a mitochondrial-localized pool of glucose-6-phosphate that triggers MondoA translocation and transcriptional induction of TXNIP to reduce glucose uptake.

    “Thus, competition between oxidative substrates might increase a mitochondrial-localized pool of glucose-6-phosphate that in turn triggers MondoA translocation and transcriptional induction of TXNIP to reduce uptake of unwanted glucose fuel (Figure 1).”
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    • Rests on an assumption: In skeletal muscle, TXNIP gene expression is controlled by MondoA.

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

    Premisecitation

    Sulfur switches have regulatory roles in cell signaling and metabolic control.

    “These so-called “sulfur switches” are gaining increasing recognition for their regulatory roles in cell signaling and metabolic control (Hui et al., 2008; Jones, 2008)”
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    Interpretationreasoning

    Chronic overabundance of nutrients leads to persistent pressure on the electron transport chain and resultant disruption of redox balance and ROS signaling.

    “This sets the stage for a highly plausible scenario wherein chronic overabundance of these nutrients leads to persistent pressure on the ETC and resultant disruption of redox balance and ROS-signaling.”
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    Interpretationcitation

    Heightened flux through FAD-linked enzyme complexes, in the absence of high ATP demand, elevates reducing pressure and increases ROS production.

    “heightened flux through the foregoing enzyme complexes, in the absence of high ATP demand (i.e. exercise), is predicted to elevate reducing pressure within the system, particularly the backpressure on complex I, thereby increasing ROS production (reviewed in (Fisher-Wellman and Neufer, (in press)) (Figure 1).”
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    Premisecitation

    In lean but severely insulin resistant muscle-specific PPARα transgenic mice, administration of the CPT-1 inhibitor oxfenicine blocked fatty acid oxidation and rescued insulin sensitivity, despite inducing profound lipid accumulation in muscle.

    “In the lean but severely insulin resistant muscle-specific PPARα transgenic mice, administration of the CPT-1 inhibitor oxfenicine blocked fatty acid oxidation and rescued insulin sensitivity, despite inducing profound lipid accumulation in muscle (Finck et al., 2005).”
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    Premisecitation

    Sulfur switches form an intracellular redox circuit linking mitochondrial H2O2 emission to control of redox-sensitive phosphatases that target the insulin signaling pathway.

    “have recently been suggested to form an intracellular redox circuit linking mitochondrial H2O2 emission to the control of redox-sensitive phosphatases that target the insulin signaling pathway (reviewed in (Fisher-Wellman and Neufer, (in press))).”
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    Premisecitation

    Muscles of Sirt3 knockout mice have increased acetylation of LCAD, SOD2, and several ETC complexes, accompanied by elevated acylcarnitines, TBARS, and pJNK.

    “muscles of Sirt3 knockout mice have increased acetylation of LCAD, SOD2 and several ETC complexes, which is accompanied by elevated acylcarnitines, TBARS and pJNK (Jing et al., 2011; Qiu et al., 2010).”
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    Premisecitation

    Sirt3 is an established deacetylase whose targets include LCAD, succinate dehydrogenase, and SOD2.

    “Sirt3 is an established deacetylase whose targets include long chain acyl CoA dehydrogenase (LCAD), succinate dehydrogenase and Mn superoxide dismutase (SOD2) (Hirschey et al., 2010; Qiu et al., 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hirschey et al., 2010 source

      Not checked in the free run.

    • cites Qiu et al., 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    A unifying mechanism of nutrient-induced insulin resistance seems improbable given the pathophysiological complexities of the disorder.

    “Although a unifying mechanism of nutrient-induced insulin resistance seems improbable given the pathophysiological complexities of the disorder”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Increasing flux through β-oxidation without a corresponding boost in energy demand imposes unwarranted reducing pressure on the respiratory system, which impinges upon redox balance and insulin action.

    “increasing flux through β-oxidation without a corresponding boost in energy demand imposes unwarranted reducing pressure on the respiratory system, which in turn impinges upon redox balance and insulin action.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    If flux through β-oxidation increases as a consequence of energy demand, the system operates in metabolic balance and insulin sensitivity is maintained.

    “Conversely, if flux through β-oxidation increases as a consequence of energy demand, the system then operates in metabolic balance and insulin sensitivity is maintained.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    The relative contributions of various stress sensing mechanisms to the origin and progression of insulin resistance likely depend on tissue specificity, diet composition, and genetic predisposition.

    “The relative contributions of various stress sensing mechanisms to the origin and progression of insulin resistance is likely to depend on tissue specificity, diet composition and genetic predisposition.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Chronic exposure to adverse metabolic conditions imposes a persistent nutrient burden on most, if not all, subcellular compartments, leading inevitably to cellular distress and dysfunction at multiple levels.

    “Chronic exposure to these adverse metabolic conditions imposes a persistent nutrient burden on most, if not all, subcellular compartments, leading inevitably to cellular distress and dysfunction at multiple levels.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The recent surge in the prevalence of insulin resistance stems largely from inactivity, caloric excess, and poor nutrient quality of heavily processed foods.

  • May combine two claims.

    Interpretationreasoning

    Mitochondrial ROS production is a common denominator that factors into each of the nutrient stress mechanisms and can be positioned both upstream and downstream of cellular insults.

    “one common denominator that factors into each of the foregoing nutrient stress mechanisms is mitochondrial ROS production, which can be positioned both upstream and downstream of the foregoing cellular insults.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Correction of this imbalance by lowering carbon import, increasing the rate of energy expenditure, or enhancing rates of carbon efflux restored both mitochondrial energetic balance and systemic glucose tolerance.

    “correction of this imbalance by one of three disparate strategies (lowering carbon import, increasing the rate of energy expenditure or enhancing rates of carbon efflux) restored both mitochondrial energetic balance and systemic glucose tolerance (Koves et al., 2005; Koves et al., 2008; Noland et al., 2009).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Koves et al., 2005 source

      Not checked in the free run.

    • cites Koves et al., 2008 source

      Not checked in the free run.

    • cites Noland et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    ROS signaling might serve as a critical site of convergence and a potential avenue for nutraceutical and/or pharmaceutical intervention.

    “ROS signaling might serve as a critical site of convergence and a potential avenue for nutraceutical and/or pharmaceutical intervention.”
    Quote in the paperNot a substantial claim
55 of 55

  • The paper relies on this without support.

    Mitochondrial respiration in all cells is governed by energy demand, including basal or idling respiratory activity and ATP regeneration.

    “Mitochondrial respiration in all cells is governed by energy demand; i.e., the energy utilized to support the basal or “idling” activity of the respiratory system plus that required for ATP regeneration.”

  • The paper relies on this without support.

    Oxidative phosphorylation is rarely operating at maximal capacity.

    “oxidative phosphorylation is rarely operating at maximal capacity”

  • The paper relies on this without support.

    Intracellular lipids accumulate whenever fatty acid supply exceeds cellular energy needs.

    “intracellular lipids amass whenever the supply of fatty acids exceeds the energy needs of the cell”

  • The paper relies on this without support.

    Supply must adjust to demand, not the reverse.

    “In other words, supply must adjust to demand, not vice versa.”

  • The paper relies on this without support.

    Acylcarnitines are generally viewed as byproducts of mitochondrial metabolism that report on cellular fluctuations in substrate supply and flux limitations at specific catabolic enzymes.

    “These metabolites are generally viewed as byproducts of mitochondrial metabolism that report on cellular fluctuations in substrate supply and flux limitations at specific catabolic enzymes.”

  • The paper relies on this without support.

    The genetic approaches used in CPT-1 overexpression studies yield notoriously poor transfection efficiencies.

    “the genetic approaches used in these studies yield notoriously poor transfection efficiencies”

  • The paper relies on this without support.

    Acylcarnitines can traverse cellular membranes, unlike their acyl-CoA precursors.

    “Unlike their acyl-CoA precursors, acylcarnitines can traverse cellular membranes.”

  • The paper relies on this without support.

    Interconversion of acyl-CoA and acylcarnitines is thought to play a key role in regulating mitochondrial acyl-CoA balance.

    “Accordingly, interconversion of these molecules is thought to play a key role in regulating mitochondrial acyl-CoA balance.”

  • The paper relies on this without support.

    In skeletal muscle, TXNIP gene expression is controlled by MondoA.

    “In skeletal muscle, TXNIP gene expression is controlled by MondoA”

  • The paper relies on this without support.

    ROS signaling and redox sensing rely heavily on the interdependent glutathione and thioredoxin reducing systems.

    “ROS signaling and redox sensing rely heavily on the interdependent glutathione and thioredoxin reducing systems.”

  • The paper relies on this without support.

    The glutathione and thioredoxin systems use the reducing power of NADPH to mitigate oxidative stress and modulate reversible oxidation/reduction of protein thiols/disulfides.

    “Both use the reducing power of NADPH to mitigate oxidative stress and to modulate reversible oxidation/reduction of protein thiols/disulfides.”

  • The paper relies on this without support.

    At least 20% of the mitochondrial proteome is acetylated.

    “at least 20% of the mitochondrial proteome is acetylated.”

  • The paper relies on this without support.

    Every major pathway of intermediary metabolism is represented among the list of acetylated proteins.

    “every major pathway of intermediary metabolism was represented among the list of acetylated proteins.”

  • The paper relies on this without support.

    Sirt3, sirt4, and sirt5 localize to mitochondria.

    “three members of the sirtuin family of deacetylases; sirt3, sirt4 and sirt5, which localize to the mitochondria.”

  • The paper relies on this without support.

    Nearly all transgenic mouse models resistant to high-fat diet-induced obesity and insulin resistance have elevated whole-body VO2 with similar or even greater food intake relative to wildtype littermates.

    “nearly all of these models have elevated whole-body VO2 with similar or even greater food intake relative their wildtype littermates.”

  • The paper relies on this without support.

    Many of the same genetic manipulations result in activation of AMPK.

    “many of the same genetic manipulations resulted in the activation of 5’AMP-activated kinase (AMPK)”

  • The paper relies on this without support.

    Cellular and mitochondrial bioenergetics is governed by the rate of energy expenditure.

    “cellular and mitochondrial bioenergetics is governed by the rate of energy expenditure”

  • The paper relies on this without support.

    The recent surge in the prevalence of insulin resistance stems largely from inactivity, caloric excess, and poor nutrient quality of heavily processed foods.

    “the recent surge in the prevalence of insulin resistance stems largely from inactivity, caloric excess and the poor nutrient quality of heavily processed foods.”

  • The paper relies on this without support.

    Dietary modification and habitual exercise are undeniably effective in combatting nutrient overload.

    “The two therapies that are undeniably effective in combatting nutrient overload include dietary modification and habitual exercise.”
19 of 19

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Authors
Muoio, D. M., & Neufer, P. D.
Affiliations
  • Duke University (US)
  • East Carolina University (US)
Corresponding author
Muoio, Deborah M.
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2012-05
Volume
15
Issue
5
Pages
595-605
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2012.04.010
PMC
PMC3348508
OpenAlex
W2032264012
Cited by
343
References
122
Citations by year
2026: 13 · 2025: 16 · 2024: 14 · 2023: 16 · 2022: 9 · 2021: 38 · 2020: 23 · 2019: 20 · 2018: 36 · 2017: 25 · 2016: 34 · 2015: 29 · 2014: 30 · 2013: 31 · 2012: 9
FWCI
12.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01AG028930)
  • National Heart, Lung, and Blood Institute (R01 HL101189R01, R01HL101189)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P01DK058398, R01DK073488, DK-073488, R01DK074825, R01DK089312)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
mitochondrial stress, lipid metabolism, skeletal muscle insulin sensitivity, insulin resistance, mitochondrial oxidative capacity, fat oxidation, acylcarnitines, mitochondrial hydrogen peroxide, redox signaling, skeletal muscle
MeSH terms
Animals, Humans, Insulin, Mitochondria, Mitochondria, Muscle, Oxidative Stress, Lipid Metabolism, Mice

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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