Linking mitochondrial bioenergetics to insulin resistance via redox biology
Open accessAbstract
Chronic overnutrition and physical inactivity are major risk factors for insulin resistance and type 2 diabetes. Recent research indicates that overnutrition generates an increase in hydrogen peroxide (H(2)O(2)) emission from mitochondria, serving as a release valve to relieve the reducing pressure created by fuel overload, as well as a primary signal that ultimately decreases insulin sensitivity. H(2)O(2) is a major input to cellular redox circuits that link to cysteine residues throughout the entire proteome to regulate cell function. Here we review the principles of mitochondrial bioenergetics and redox systems biology and offer new insight into how H(2)O(2) emission may be linked via redox biology to the etiology of insulin resistance.
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Sustained energy surplus raises mitochondrial metabolic by-products that could contribute to the development of insulin resistance and metabolic inflexibility.
“Emergent evidence suggests that a chronic positive energy balance increases by-products of mitochondrial metabolism that may trigger the pathogenesis of insulin resistance and metabolic inflexibility (16,17).”
From Defects in mitochondrial efficiency and H2O2 emissions in obese women are restored to a lean phenotype with aerobic exercise training (2015) · cites this paper as [17]
A nutrient surplus generates a positive mitochondrial membrane potential, raising mtH2O2 emissions.
“The nutrient burden creates a positive mitochondrial membrane potential, which increases mtH2O2 emissions (17), and chronic exposure to reactive oxygen species has been shown to inhibit insulin-mediated GLUT4 translocation (26).”
From Defects in mitochondrial efficiency and H2O2 emissions in obese women are restored to a lean phenotype with aerobic exercise training (2015) · cites this paper as [17]
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“Moreover, insulin regulates mitochondrial metabolism and oxidative capacity throughPI3K/Akt signaling [36, 37]; therefore, decreased Akt signaling by hyperinsulinemia- mediated IR may have profound effects on mitochondrial function in neurons and result in subsequent increased oxidative stress [38].”
BackgroundThe rise of mitochondria in medicine
Picard, M. A., Wallace, D. C., & Burelle, Y. (2016) · Mitochondrion · doi:10.1016/j.mito.2016.07.003 · Cited by 454 · see citing works
“The detrimental effect of metabolic oversupply is thought to result from mitochondrial substrate overload (Fisher-Wellman and Neufer, 2012), which entails excessive reduction of the respiratory chain and consequent ROS production (Anderson et al., 2009), mitochondrial fission and oxidative stress…”
BackgroundMitochondrial dysfunction in type 2 diabetes mellitus: an organ-based analysis
Pinti, M. V., Fink, G. K., Hathaway, Q. A., Durr, A. J., Kunovac, A., & Hollander, J. M. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00314.2018 · Cited by 432 · see citing works
“The role of mitochondrial dysfunction is of particular importance in T2DM due to its established association with insulin resistance, as previously reviewed (58, 105, 116, 152, 190).”
BackgroundPGC-1α-mediated regulation of mitochondrial function and physiological implications
Halling, J. F., & Pilegaard, H. (2020) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2020-0005 · Cited by 418 · see citing works
“This model predicts that excess energy intake or sedentary behavior, resulting in prolonged positive energy balance, may cause pathological oxidative damage to tissues (Fisher-Wellman & Neufer, 2012).”
BackgroundMitochondrial metabolism mediates oxidative stress and inflammation in fatty liver
Satapati, S., Kucejová, B., Duarte, J. A. G., Fletcher, J. A., Reynolds, L., Sunny, N. E., He, T., Nair, L. A., Livingston, K. A., Fu, X., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci82204 · Cited by 400 · see citing works
“org Volume 125 Number 12 December 2015 tection from elevated GNG could be explained by lower capacity in the knockdown mice, but protected insulin action likely stems from secondary factors such as reduced oxidative stress, inflammation, and/or altered redox signaling (53, 61).”
BackgroundPathogenesis of Chronic Hyperglycemia: From Reductive Stress to Oxidative Stress
Yan, L. (2014) · Journal of Diabetes Research · doi:10.1155/2014/137919 · Cited by 403 · see citing works
Liver glucose metabolism in humans
Adeva-Andany, M. M., Pérez-Felpete, N., Fernández-Fernández, C., Donapetry-García, C., & Pazos-García, C. (2016) · Bioscience Reports · doi:10.1042/bsr20160385 · Cited by 372 · see citing works
Höhn, A., Weber, D., Jung, T., Ott, C., Hugo, M., Kochlik, B., Kehm, R., König, J., Grune, T., & Castro, J. P. (2016) · Redox Biology · doi:10.1016/j.redox.2016.12.001 · Cited by 368 · see citing works
“Dysfunctional mitochondria leak electrons and generate O2 •− as by-products, especially, on the complex I (NADH dehydrogenase) and complex III (Cytochrome bc1 complex) [43].”
BackgroundMitochondrial dysfunction in white adipose tissue
Kusminski, C. M., & Scherer, P. E. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.06.004 · Cited by 368 · see citing works
“For instance, O2· is considered the primary ROS species, with H2O2 a potent downstream secondary messenger [24].”
Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle
Muoio, D. M., & Neufer, P. D. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.010 · Cited by 343 · see citing works
Self-citationSkeletal muscle insulin resistance: role of mitochondria and other ROS sources
Di Meo, S., Iossa, S., & Venditti, P. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0598 · Cited by 282 · see citing works
“In this situation, the reverse electron flow from coenzyme Q (Ernster & Lee 1967) would bring complex I to a more reduced state, thus enhancing the probability that electrons catalyzing univalent reduction of O 2 are released (Fisher-Wellman & Neufer 2012).”
BackgroundMitochondrial and cellular mechanisms for managing lipid excess
Aon, M. A., Bhatt, N., & Cortassa, S. C. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00282 · Cited by 253 · see citing works
“…vital functions such as division, differentiation, contractile work and survival amongst others (Schafer and Buettner, 2001; Aon et al., 2007, 2009; Brown et al., 2010; Fisher-Wellman and Neufer, 2012; Jeong et al., 2012; Lloyd et al., 2012; Muoio and Neufer, 2012; Aggarwal and Makielski, 2013).”
BackgroundInfluentialCappel, D. A., Deja, S., Duarte, J. A. G., Kucejova, B., Iñigo, M., Fletcher, J. A., Fu, X., Berglund, E. D., Liu, T., Elmquist, J. K., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.03.014 · Cited by 242 · see citing works
“Loss of NADPH, in turn, inhibits free radical scavenging by the glutathione and thioredoxin systems (Fisher-Wellman and Neufer, 2012), and deactivates catalase (Kirkman et al.”
BackgroundAcylcarnitines: potential implications for skeletal muscle insulin resistance
Aguer, C., McCoin, C. S., Knotts, T. A., Thrush, A. B., Ono‐Moore, K. D., McPherson, R., Dent, R., Hwang, D. H., Adams, S. H., & Harper, M. (2014) · The FASEB Journal · doi:10.1096/fj.14-255901 · Cited by 243 · see citing works
“However, it is likely that a greater proportion of reducing equivalents produced from fatty acid b-oxidation enter the electron transport chain at the electron transfer flavoprotein, thus bypassing complex I, the main ROS production site (8, 9).”
BackgroundLepretti, M., Martucciello, S., Burgos Aceves, M., Putti, R., & Lionetti, L. (2018) · Nutrients · doi:10.3390/nu10030350 · Cited by 232 · see citing works
“In this case, insulin resistance is suggested to be caused by the production/emission of mitochondrial oxidants due to excess fuel within mitochondria in the absence of increased energy demand [37] (Figure 1).”
BackgroundLipids, lysosomes, and autophagy
Jaishy, B. P., & Abel, E. D. (2016) · Journal of Lipid Research · doi:10.1194/jlr.r067520 · Cited by 229 · see citing works
“These include imposes constant pressure on the mitochondrial electron transport chain to increase electron flux, which increases reactive oxygen species (ROS) production from electron transport chain complexes I and III (14).”
InfluentialFrom OCR and ECAR to energy: Perspectives on the design and interpretation of bioenergetics studies
Schmidt, C. A., Fisher‐Wellman, K. H., & Neufer, P. D. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101140 · Cited by 197 · see citing works
Self-citationFatty acid metabolism, energy expenditure and insulin resistance in muscle
Turner, N. A., Cooney, G. J., Kraegen, E. W., & Bruce, C. R. (2013) · Journal of Endocrinology · doi:10.1530/joe-13-0397 · Cited by 198 · see citing works
Epigenetics and Oxidative Stress in Aging
Guillaumet-Adkins, A., Yáñez, Y., Peris‐Díaz, M. D., Calabria, I., Palanca-Ballester, C., & Sandoval, J. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/9175806 · Cited by 194 · see citing works
“− as by-products, especially on the complex I (NADH dehydrogenase) and complex III (cytochrome bc 1 complex) [24].”
BackgroundMuscle and adipose tissue insulin resistance: malady without mechanism?
Fazakerley, D. J., Krycer, J. R., Kearney, A. L., HOCKING, S. L., & James, D. E. (2018) · Journal of Lipid Research · doi:10.1194/jlr.r087510 · Cited by 181 · see citing works
“The authors also thank Associate Professor Kyle Hoehn (University of New South Wales, Sydney, Australia), Professor Gregory Cooney (University of Sydney, Sydney, Australia), and Professor P. Darrell Neufer (East Carolina University, Greenville, NC) for critical reading of the manuscript and helpful comments”
BackgroundInfluentialTorres, M. J., Kew, K. A., Ryan, T. E., Pennington, E. R., Lin, C.-T., Buddo, K. A., Fix, A. M., Smith, C. A., Gilliam, L. A., Karvinen, S., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.10.003 · Cited by 170 · see citing works
Self-citationHigh Dietary Fat Selectively Increases Catalase Expression within Cardiac Mitochondria
Rindler, P. M., Plafker, S. M., Szweda, L. I., & Kinter, M. T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.412890 · Cited by 168 · see citing works
“Several different mechanisms of free radical production have been implicated in obesity, including the release of pro-inflammatory adipokines (12), elevated NAD(P)H oxidase activity (13), and increased mitochondrial hydrogen peroxide (H2O2) production (14, 15).”
BackgroundMethods for Assessing Mitochondrial Function in Diabetes
Perry, C. G. R., Kane, D. A., Lanza, I. R., & Neufer, P. D. (2013) · Diabetes · doi:10.2337/db12-1219 · Cited by 165 · see citing works
Self-citationRedox-Optimized ROS Balance and the relationship between mitochondrial respiration and ROS
Cortassa, S. C., O'Rourke, B. P., & Aon, M. A. (2013) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2013.11.007 · Cited by 156 · see citing works
“The role of mitochondrial functions pertains not only to pathology but also to vital physiological activities, such as exercise and nutrition [12].”
Tipping the metabolic scales towards increased longevity in mammals
Riera, C. E., & Dillin, A. (2015) · Nature Cell Biology · doi:10.1038/ncb3107 · Cited by 153 · see citing works
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The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction
Castro, J. P., Grune, T., & Speckmann, B. (2016) · Biological Chemistry · doi:10.1515/hsz-2015-0305 · Cited by 152 · see citing works
Adipose oxidative stress and protein carbonylation
Hauck, A. K., Huang, Y., Hertzel, A. V., & Bernlohr, D. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.r118.003214 · Cited by 152 · see citing works
“Fisher-Wellman and Neufer (15) have posited a novel hypothesis that under conditions of low reduced GSH, common to fat cells from insulin-resistant states, pyruvate dehydrogenase and nicotinamide nucleotide transhydrogenase form a redox circuit with the potential to be a robust generator of H2O2.”
BackgroundNisr, R. B., Shah, D. S., Ganley, I. G., & Hundal, H. S. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03148-8 · Cited by 142 · see citing works
Oxidative Shielding or Oxidative Stress?
Naviaux, R. K. (2012) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.192120 · Cited by 139 · see citing works
“The partial reduction of oxygen to superoxide and peroxide serves as a “pressure release valve”(Fisher-Wellman and Neufer, 2012), that permits excess electrons to be dissipated and excess oxygen to be exported from the cell in the form of soluble hydrogen peroxide.”
BackgroundLionaki, E., Markaki, M., Palikaras, K., & Tavernarakis, N. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.04.010 · Cited by 134 · see citing works
“PINK1 overexpression rescues the abnormal mitochondrial morphology, ATP levels and enhances survival of flies expressing mutant huntingtin in neurons [203].”
BackgroundInfluentialNonalcoholic fatty liver disease: a challenge from mechanisms to therapy.
Tarantino, G., Citro, V., & Capone, D. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm9010015 · Cited by 134 · see citing works
“Mitochondria are clearly considered to be main contributors to oxidative stress in obesity induced by chronic over-nutrition, with subsequent reduced insulin sensitivity or IR [6].”
BackgroundStress-induced FGF21 and GDF15 in obesity and obesity resistance
Keipert, S., & Ost, M. (2021) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2021.08.008 · Cited by 131 · see citing works
Diabetes: Have We Got It All Wrong?
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Novel approach to quantify mitochondrial content and intrinsic bioenergetic efficiency across organs
McLaughlin, K., Hagen, J. T., Coalson, H. S., Nelson, M. A. M., Kew, K. A., Wooten, A., & Fisher‐Wellman, K. H. (2020) · Scientific Reports · doi:10.1038/s41598-020-74718-1 · Cited by 129 · see citing works
Self-citationRedox basis of exercise physiology
Margaritelis, N. V., Paschalis, V., Theodorou, A. A., Kyparos, A., & Nikolaidis, M. G. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101499 · Cited by 129 · see citing works
“tabolic molecules, such as protein kinases and phosphatases [66,394].”
BackgroundFisher‐Wellman, K. H., Lin, C., RYAN, T. E., Reese, L., Gilliam, L. A. A., Cathey, B. L., Lark, D. S., Smith, C. D., Muoio, D. M., & Neufer, P. D. (2015) · Biochemical Journal · doi:10.1042/bj20141447 · Cited by 121 · see citing works
“, superoxide anion (O2•)/hydrogen peroxide (H2O2)) that effectively regulates overall cellular redox charge [4].”
BackgroundSelf-citationA Direct Comparison of Metabolic Responses to High-Fat Diet in C57BL/6J and C57BL/6NJ Mice
Fisher‐Wellman, K. H., RYAN, T. E., Smith, C. D., Gilliam, L. A. A., Lin, C., Reese, L., Torres, M. J., & Neufer, P. D. (2016) · Diabetes · doi:10.2337/db16-0291 · Cited by 117 · see citing works
“, NADPH) rather than H2O2 production per se (18,37).”
BackgroundSelf-citationFisher‐Wellman, K. H., Gilliam, L. A. A., Lin, C., Cathey, B. L., Lark, D. S., & Neufer, P. D. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.09.008 · Cited by 115 · see citing works
“The rate of H2O2 generation relative to flux throughout the redox buffering networks determines the redox status of cysteine containing proteins throughout the cell, thereby conferring regulation to various redox-sensitive cell processes [8, 9], including insulin sensitivity [10].”
Self-citationKonopka, A. R., Asante, A., Lanza, I. R., Robinson, M. M., Johnson, M. L., Dalla Man, C., Cobelli, C., Amols, M. H., Irving, B. A., & Nair, K. S. (2015) · Diabetes · doi:10.2337/db14-1701 · Cited by 112 · see citing works
“Emergent evidence suggests that a chronic positive energy balance increases by-products of mitochondrial metabolism that may trigger the pathogenesis of insulin resistance and metabolic inflexibility (16,17).”
BackgroundThe role of mitochondria in the aetiology of insulin resistance and type 2 diabetes
Martin, S. D., & McGee, S. L. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.09.019 · Cited by 112 · see citing works
Gilliam, L. A. A., Fisher‐Wellman, K. H., Lin, C., Maples, J. M., Cathey, B. L., & Neufer, P. D. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.08.191 · Cited by 113 · see citing works
“The electron carriers of the mitochondrial ETS drive the translocation of protons across the inner membrane, creating a proton motive force composed of both a chemical and electrical gradient [37].”
BackgroundSelf-citationGurzov, E. N., Tran, M., Fernandez-Rojo, M. A., Merry, T. L., Zhang, X., Xu, Y., Fukushima, A., Waters, M. J., Watt, M. J., Andrikopoulos, S., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.05.011 · Cited by 111 · see citing works
“H2O2 is thereon eliminated by antioxidant enzymes such catalase, peroxiredoxins, and glutathione peroxidase 1 (Gpx1) (Fisher-Wellman and Neufer, 2012).”
BackgroundInfluence of exercise intensity on systemic oxidative stress and antioxidant capacity
Parker, L., McGuckin, T., & Leicht, A. S. (2013) · Clinical Physiology and Functional Imaging · doi:10.1111/cpf.12108 · Cited by 110 · see citing works
“…intake and sedentary behaviour have been reported to induce chronic levels of ROS and result in pathological responses such as insulin resistance (Fisher-Wellman & Neufer, 2012) and other chronic lifestyle diseases (Valko et al., 2007), many of which may be alleviated by regular exercise-induced…”
BackgroundProtein Carbonylation, Mitochondrial Dysfunction, and Insulin Resistance
Frohnert, B. I., & Bernlohr, D. (2013) · Advances in Nutrition · doi:10.3945/an.112.003319 · Cited by 110 · see citing works
“Furthermore, the rate at which superoxide oxidizes thiols is relatively slow compared with its rate of catalysis by MnSOD (2), making it more likely a precursor rather than the primary second messenger connecting oxidative stress to insulin resistance.”
BackgroundInfluentialAccattato, F., Greco, M., Pullano, S. A., Carè, I., Fiorillo, A. S., Pujia, A., Montalcini, T., FOTI, D. P., Brunetti, A., & Gulletta, E. (2017) · PLoS ONE · doi:10.1371/journal.pone.0178900 · Cited by 109 · see citing works
Han, X., Zhao, S., Song, H., Xu, T., Fang, Q., Hu, G., & Sun, L. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101911 · Cited by 105 · see citing works
Enzymes involved in l-lactate metabolism in humans
Adeva‐Andany, M. M., González-Lucán, M., Seco-Cervera, M., & Donapetry, C. (2013) · Mitochondrion · doi:10.1016/j.mito.2013.08.011 · Cited by 98 · see citing works
Obesogens: a unifying theory for the global rise in obesity
Heindel, J. J., Lustig, R. H., Howard, S. G., & Corkey, B. E. (2024) · International Journal of Obesity · doi:10.1038/s41366-024-01460-3 · Cited by 100 · see citing works
“These proteins, in turn, regulate cellular signal transduction, including endocrine secretion and energy homeostasis [73].”
BackgroundPhysical inactivity, insulin resistance, and the oxidative-inflammatory loop
Gratas-Delamarche, A., Derbré, F., Vincent, S., & Cillard, J. (2014) · Free Radical Research · doi:10.3109/10715762.2013.847528 · Cited by 99 · see citing works
p38 MAPK in Glucose Metabolism of Skeletal Muscle: Beneficial or Harmful?
Bengal, E., Aviram, S., & Hayek, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186480 · Cited by 98 · see citing works
“Another model predicts that calorie surplus imposes maximal mitochondrial respiration and leakage of electrons from the electron transport chain, forming oxygen radicals [69].”
BackgroundWang, C., & Wei, Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155266 · Cited by 95 · see citing works
“Oxidative stress derived from mitochondrial overload is well known as an underlying mechanism of insulin resistance [9].”
BackgroundNO-Rich Diet for Lifestyle-Related Diseases
Kobayashi, J., Ohtake, K., & Uchida, H. (2015) · Nutrients · doi:10.3390/nu7064911 · Cited by 94 · see citing works
Mitochondrial alteration in type 2 diabetes and obesity: An epigenetic link
Cheng, Z., & Almeida, F. A. (2014) · Cell Cycle · doi:10.4161/cc.28189 · Cited by 94 · see citing works
“1).(2,5,7,8) Accordingly, a decrease in mitochondrial function or mitochondrial DNA (mtDNA) copy number has been correlated with insulin resistance and dysregulated lipid metabolism.”
BackgroundRedox implications in adipose tissue (dys)function-A new look at old acquaintances
Jankovic, A., Korac, A., Buzadzic, B., Otasevic, V., Stancic, A., Daiber, A., & Korac, B. (2015) · Redox Biology · doi:10.1016/j.redox.2015.06.018 · Cited by 91 · see citing works
“H2O2 emission in different cells serves as both, an estimate of energy balance and as a determining factor of cellular redox environment, thus linking cellular metabolic balance to the control of their insulin sensitivity [51,78].”
BackgroundPutti, R., Migliaccio, V., Sica, R., & Lionetti, L. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2015.00426 · Cited by 90 · see citing works
“In recent years, different reviews focused on mechanism(s) by which mitochondrial bioenergetics (Fisher-Wellman and Neufer, 2012; Lark et al., 2012; Muoio and Neufer, 2012; Holloszy, 2013) and morphology (Liesa and Shirihai, 2013; Montgomery and Turner, 2015) may be linked to the etiology of IR in…”
BackgroundMitoNEET-mediated effects on browning of white adipose tissue
Kusminski, C. M., Park, J., & Scherer, P. E. (2014) · Nature Communications · doi:10.1038/ncomms4962 · Cited by 84 · see citing works
Mitochondrial fission mediates ceramide-induced metabolic disruption in skeletal muscle
Smith, M. E., Tippetts, T. S., Brassfield, E. S., Tucker, B. J., Ockey, A., Swensen, A. C., Anthonymuthu, T. S., Washburn, T. D., Kane, D. A., Prince, J. T., et al. (2013) · Biochemical Journal · doi:10.1042/bj20130807 · Cited by 87 · see citing works
Alleman, R. J., Katunga, L. A., Nelson, M. A. M., Brown, D. A., & Anderson, E. J. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00358 · Cited by 84 · see citing works
“…Research September 2014 | Volume 5 | Article 358 | 2 and recruitment of immune cells, activation of pro-fibrotic gene expression and cardiac hypertrophy, increased cell death, and insulin resistance (reviewed in Fisher-Wellman and Neufer, 2012; Cavalera et al., 2014; Dai et al., 2014).”
BackgroundOxidative toxicology of bleomycin: Role of the extracellular redox environment
Allawzi, A. M., Elajaili, H. B., Redente, E. F., & Nozik‐Grayck, E. (2018) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2018.08.001 · Cited by 83 · see citing works
PGC-1α regulates mitochondrial properties beyond biogenesis with aging and exercise training
Halling, J. F., Jessen, H., Nøhr-Meldgaard, J., Buch, B. T., Christensen, N. M., Gudiksen, A., Ringholm, S., Neufer, P. D., Prats, C., & Pilegaard, H. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00059.2019 · Cited by 82 · see citing works
Self-citationCortassa, S. C., Sollott, S. J., & Aon, M. A. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005588 · Cited by 76 · see citing works
Moghaddam, H. S., Sherbaf, F. G., & Aarabi, M. H. (2019) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2019.100782 · Cited by 74 · see citing works
Compromised DNA repair is responsible for diabetes‐associated fibrosis
Kumar, V., Agrawal, R., Pandey, A., Kopf, S., Höffgen, M., Kaymak, S., Bandapalli, O. R., Gorbunova, V. A., Seluanov, A., Mall, M. A., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2019103477 · Cited by 74 · see citing works
“Therefore, it interferes with the normal functioning of mitochondria, thus generates H 2 O 2, as well as highly reactive superoxide anions, which further compromises the cellular physiology (Fisher-Wellman & Neufer, 2012).”
Quercetin alleviates ethanol-induced liver steatosis associated with improvement of lipophagy
Zeng, H., Guo, X., Zhou, F., Xiao, L., Liu, J., Jiang, C., Xing, M., & Yao, P. (2018) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.12.028 · Cited by 74 · see citing works
Galizzi, G., & Carlo, M. D. (2022) · Biology · doi:10.3390/biology11060943 · Cited by 76 · see citing works
“A reduction in mitochondria respiration and bioenergetics is associated with insulin resistance [13].”
BackgroundSecondary muscle pathology and metabolic dysregulation in adults with cerebral palsy
Peterson, M. D., Gordon, P. M., Hurvitz, E. A., & Burant, C. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00338.2012 · Cited by 73 · see citing works
The Role of Oxidative Stress Enhanced by Adiposity in Cardiometabolic Diseases
Świątkiewicz, I., Wróblewski, M., Nuszkiewicz, J., Sutkowy, P., Wróblewska, J., & Woźniak, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076382 · Cited by 79 · see citing works
Carbonylation of proteins—an element of plant ageing
Ciacka, K., Tymiński, M., Gniazdowska, A., & Krasuska, U. (2020) · Planta · doi:10.1007/s00425-020-03414-1 · Cited by 71 · see citing works
Bakkar, N. Z., Dwaib, H. S., Fares, S. A., Eid, A. H., Al-Dhaheri, Y., & EL‐Yazbi, A. F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239005 · Cited by 74 · see citing works
“It was also shown that hyperinsulinemia can lead to increased neuronal oxidative stress through decreased mitochondrial PI3K/Akt signaling pathway [40].”
BackgroundProtein Carbonylation and Adipocyte Mitochondrial Function
Curtis, J. M., Hahn, W. S., Stone, M. D., Inda, J. J., Droullard, D. J., Kuzmicic, J., Donoghue, M. A., Long, E. K., Armién, A. G., Lavandero, S., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.400663 · Cited by 71 · see citing works
Mitochondrial involvement in skeletal muscle insulin resistance: A case of imbalanced bioenergetics
Affourtit, C. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.07.008 · Cited by 67 · see citing works
“4), and it is argued that the phenotype depends on the strength and persistence of the H2O2 signal [53].”
InfluentialProtective Mechanisms of Mitochondria and Heart Function in Diabetes
Aon, M. A., Tocchetti, C. G., Bhatt, N., Paolocci, N., & Cortassa, S. C. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6123 · Cited by 70 · see citing works
“The debate centers around the role of mitochondrial lipid oxidation capacity and its impact on ROS emission and insulin signaling (71, 126, 137, 173).”
The Redox Communication Network as a Regulator of Metabolism
Corkey, B. E., & Deeney, J. T. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.567796 · Cited by 70 · see citing works
Merry, T. L., Tran, M., Stathopoulos, M., Wiede, F., Fam, B. C., Dodd, G. T., Clarke, I. J., Watt, M. J., Andrikopoulos, S., & Tiganis, T. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5428 · Cited by 69 · see citing works
“Increased mitochondrial reactive oxygen species (ROS) production is a major contributor to the oxidative stress in obesity (1, 25).”
Mailloux, R. J., Fu, A., Robson-Doucette, C., Allister, E. M., Wheeler, M. B., Screaton, R., & Harper, M.-E. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.393538 · Cited by 66 · see citing works
“Redox biology was recently suggested to play a key role in insulin signaling and release (36).”
Background2-Aminoadipic acid (2-AAA) as a potential biomarker for insulin resistance in childhood obesity
Lee, H., Jang, H. B., Kim, W., Park, K. J., Kim, K. Y., Park, S. I., & Lee, H. J. (2019) · Scientific Reports · doi:10.1038/s41598-019-49578-z · Cited by 63 · see citing works
Fisher‐Wellman, K. H., Mattox, T. A., Thayne, K. A., Katunga, L. A., Favor, J. D. L., Neufer, P. D., Hickner, R. C., Wingard, C. J., & Anderson, E. J. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.254193 · Cited by 62 · see citing works
“The ability of increased H2O2 to alter protein function and thereby contribute to metabolic disease stems from its integration into and regulation of various redox signalling networks operating within the cell (Adimora et al. 2010; Fisher-Wellman & Neufer, 2012).”
BackgroundSelf-citationImprovement of obesity-linked skeletal muscle insulin resistance by strength and endurance training
Meo, S. D., Iossa, S., & Venditti, P. (2017) · Journal of Endocrinology · doi:10.1530/joe-17-0186 · Cited by 62 · see citing works
“This idea is consistent with the suggested close relationship between oxidative stress and IR (Fisher-Wellman & Neufer 2012).”
ResultDietary nitrite supplementation improves insulin resistance in type 2 diabetic KKAy mice
Ohtake, K., Nakano, G., Ehara, N., Sonoda, K., Ito, J., Uchida, H., & Kobayashi, J. (2015) · Nitric Oxide · doi:10.1016/j.niox.2014.11.009 · Cited by 63 · see citing works
“Many kinases and phosphatases associated with the insulin signaling pathways are intricately regulated and balanced by protein phosphorylation, dephosphorylation, and in some cases, nitrosylation [22].”
BackgroundCrosstalk between autophagy and insulin resistance: evidence from different tissues
Sadeghi, A., Niknam, M., Momeni‐Moghaddam, M. A., Shabani, M., Aria, H., Bastin, A., Teimouri, M., Meshkani, R., & Akbari, H. (2023) · European journal of medical research · doi:10.1186/s40001-023-01424-9 · Cited by 65 · see citing works
Greatorex, S., Kaur, S., Xirouchaki, C. E., Goh, P. K., Wiede, F., Genders, A., Tran, M., Jia, Y., Raajendiran, A., Brown, W., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci162533 · Cited by 50 · see citing works
“Chronic hepatic lipid accumulation in NAFLD is accompanied by increased mitochondrial O2• – and H 2 O 2 generation (9, 43).”
Zhang, H., Ma, X., Wu, L., Zhao, Y., Zhang, P.-Y., Zhang, Y., Shao, M., Liu, F., Li, F., & Qin, G.-J. (2015) · Experimental Biology and Medicine · doi:10.1177/1535370214557218 · Cited by 60 · see citing works
Physical Activity, Lifestyle Factors and Oxidative Stress in Middle Age Healthy Subjects
Carraro, E., Schilirò, T., Biorci, F., Romanazzi, V., Degan, R., Buonocore, D., Verri, M., Dossena, M., Bonetta, S., & Gilli, G. (2018) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph15061152 · Cited by 60 · see citing works
“resulting in pathological responses such as insulin resistance [7] and chronic lifestyle diseases [2], many of which may be alleviated by regular exercise-induced redox adaptations [6].”
BackgroundTargeting the NO/superoxide ratio in adipose tissue: relevance to obesity and diabetes management
Janković, A., Korać, A., Buzadžić, B., Stančić, A., Otašević, V., Ferdinándy, P., Daiber, A., & Korać, B. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13498 · Cited by 60 · see citing works
“Under normal (unstimulated or basal) circumstances, most protein Cys residues are maintained in the reduced state due to high levels and overall presence (cytoplasmic and mitochondrial) of GSH and thioredoxins (Trx), peroxiredoxins and the corresponding NADPHcoupled reductase systems (Fisher-Wellman and Neufer, 2012).”
BackgroundInfluentialDiabetic Myopathy: current molecular understanding of this novel neuromuscular disorder
Monaco, C. M. F., Perry, C. G. R., & Hawke, T. J. (2017) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000479 · Cited by 59 · see citing works
Skeletal muscle reactive oxygen species: A target of good cop/bad cop for exercise and disease
Mason, S. A., & Wadley, G. D. (2014) · Redox Report · doi:10.1179/1351000213y.0000000077 · Cited by 58 · see citing works
Lee-Ødegård, S., Olsén, T., Vinknes, K. J., Refsum, H., Gulseth, H. L., Birkeland, K. I., & Drevon, C. A. (2018) · Nutrients · doi:10.3390/nu11010010 · Cited by 57 · see citing works
“Third, cysteine is linked to redox balance [46,47], oxidative stress [47–49], glutathione biosynthesis [16], insulin sensitivity [48], glucose uptake [50], and mitochondrial function [47–49].”
BackgroundRYAN, T. E., Schmidt, C. A., Green, T. D., Spangenburg, E. E., Neufer, P. D., & McClung, J. M. (2016) · Diabetes · doi:10.2337/db16-0387 · Cited by 55 · see citing works
“However, these vascular alterations fail to adequately address the effects on the functional deficits that accompany PAD, as type 2 diabetes also reduces limb muscle quality (11,12) and contributes to mitochondrial dysfunction (13).”
BackgroundSelf-citationWilliams, A. S., Koves, T. R., Davidson, M. T., Crown, S. B., Fisher‐Wellman, K. H., Torres, M. J., Draper, J. A., Narowski, T. M., Slentz, D. H., Lantier, L., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.003 · Cited by 55 · see citing works
“In light of substantial evidence linking states of elevated mitochondrial ROS emission to the development of glucose intolerance and insulin resistance (Anderson et al., 2009; Fisher-Wellman and Neufer, 2012; Patti and Corvera, 2010), we presume that the severity of diet-induced insulin resistance in the DKO mice migh…”
BackgroundSelf-citationKramer, P. A., Duan, J., Qian, W.-J., & Marcinek, D. J. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00347 · Cited by 54 · see citing works
“Intracellular redox circuitry is regarded as a master regulator of phosphorylation and de-phosphorylation because nearly all classes of protein phosphatases and many kinases contain redox sensitive Cys residues for regulating their activities (Chiarugi, 2005; Fisher-Wellman and Neufer, 2012).”
BackgroundExercise and Glycemic Control: Focus on Redox Homeostasis and Redox-Sensitive Protein Signaling
Parker, L., Shaw, C. S., Stepto, N. K., & Levinger, I. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00087 · Cited by 55 · see citing works
“This oxidative redox environment favors the oxidation of catalytic cysteine to sulphenic acid, suppressing PTP activity and enhancing kinase activity and propagation of the insulin signaling cascade (9).”
InfluentialDrougard, A., Duparc, T., Brénachot, X., Carneiro, L., Gouazé, A., Fournel, A., Geurts, L., Cadoudal, T., Prats, A., Pénicaud, L., et al. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5182 · Cited by 54 · see citing works
“The implication of ROS/H 2 O 2 in the control of glucose metabolism in normal and physiopathological states is well established (15).”
InfluentialCrewe, C., Kinter, M. T., & Szweda, L. I. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077280 · Cited by 53 · see citing works
“A potential mechanism by which increased expression of PDK4 precipitates loss of insulin signaling is through metabolically driven changes in the redox environment [36].”
BackgroundRedox regulation of insulin sensitivity due to enhanced fatty acid utilization in the mitochondria
Rindler, P. M., Crewe, C., Fernandes, J., Kinter, M. T., & Szweda, L. I. (2013) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00799.2012 · Cited by 54 · see citing works
McKeegan, K., Mason, S. A., Trewin, A. J., Keske, M. A., Wadley, G. D., Gatta, P. A. D., Nikolaidis, M. G., & Parker, L. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102005 · Cited by 55 · see citing works
“Larger meals and meals higher in lipid content generally elicit greater postprandial oxidative stress [80,81], which are proposed to contribute to the development of acute and chronic insulin resistance [9,10,23,51].”
BackgroundInfluentialVitamin C supplementation for diabetes management: A comprehensive narrative review
Mason, S. A., Parker, L., van der Pligt, P., & Wadley, G. D. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.12.003 · Cited by 53 · see citing works
- Authors
- Fisher-Wellman, K. H., & Neufer, P. D.
- Affiliations
- East Carolina University (US)
- Corresponding author
- Neufer, P. Darrell
- ORCID
- Neufer, P. Darrell
- Venue
- Trends in Endocrinology & Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 23
- Issue
- 3
- Pages
- 142-153
- ISSN
- 1043-2760 (ISSN-L)
- PMC
- PMC3313496
- OpenAlex
- W2069466682
- Cited by
- 316
- References
- 89
- Citations by year
- 2026: 17 · 2025: 12 · 2024: 16 · 2023: 22 · 2022: 14 · 2021: 24 · 2020: 16 · 2019: 28 · 2018: 24 · 2017: 25 · 2016: 20 · 2015: 25 · 2014: 29 · 2013: 30 · 2012: 12
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Trends in Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK073488, R01DK074825)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mitochondrial bioenergetics, insulin resistance, type 2 diabetes, hydrogen peroxide, mitochondrial reactive oxygen species, redox signaling, cysteine residues, overnutrition, physical inactivity
- MeSH terms
- Animals, Energy Metabolism, Humans, Hydrogen Peroxide, Insulin Resistance, Mitochondria, Oxidation-Reduction, Signal Transduction
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