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  • Review Article
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Mitochondrial energetics in the kidney

Nature Reviews Nephrology volume 13, pages 629–646 (2017)Cite this article

Subjects

Key Points

  • Mitochondrial homeostasis requires a fine-tuned balance between mitochondrial dynamics and mitochondrial energetics, and ensures the maintenance of properly functioning mitochondria

  • Mitochondria can adapt to different metabolic conditions via the regulation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) nutrient sensing pathways, to maintain a healthy population of mitochondria

  • External stimuli can augment mitochondrial processes, such as mitophagy, fission and fusion, and mitochondrial biogenesis to attenuate irregular levels of ATP production

  • The disruption of mitochondrial homeostasis in the early stages of acute kidney injury is an important factor that drives tubular injury and persistent renal dysfunction

  • Hyperglycaemia-induced ATP depletion triggers changes in mitochondrial morphology that lead to the onset of diabetic nephropathy in diabetes mellitus

  • Correcting abnormal electron transport chain function directly, and/or by targeting the pathways that regulate mitochondrial biogenesis, is likely to improve renal outcomes by restoring mitochondrial function and stimulating organ repair

Abstract

The kidney requires a large number of mitochondria to remove waste from the blood and regulate fluid and electrolyte balance. Mitochondria provide the energy to drive these important functions and can adapt to different metabolic conditions through a number of signalling pathways (for example, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways) that activate the transcriptional co-activator peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), and by balancing mitochondrial dynamics and energetics to maintain mitochondrial homeostasis. Mitochondrial dysfunction leads to a decrease in ATP production, alterations in cellular functions and structure, and the loss of renal function. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy, as it disrupts mitochondrial homeostasis and thus normal kidney function. Improving mitochondrial homeostasis and function has the potential to restore renal function, and administering compounds that stimulate mitochondrial biogenesis can restore mitochondrial and renal function in mouse models of AKI and diabetes mellitus. Furthermore, inhibiting the fission protein dynamin 1-like protein (DRP1) might ameliorate ischaemic renal injury by blocking mitochondrial fission.

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Figure 1: ATP production in the kidney.
Figure 2: Oxidative stress and the antioxidant defence system.
Figure 3: Crosstalk between two nutrient-sensing pathways.
Figure 4: Activation and regulation of mitochondrial biogenesis.
Figure 5: Mitochondrial dynamics: fission, fusion and mitophagy.
Figure 6: Changes in mitochondrial morphology lead to tubular damage in acute kidney injury.
Figure 7: Factors contributing to mitochondrial dysfunction in diabetic nephropathy.

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References

  1. Wang, Z. M. et al. Specific metabolic rates of major organs and tissues across adulthood: evaluation by mechanistic model of resting energy expenditure. Am. J. Clin. Nutr. 92, 1369–1377 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. O'Connor, P. M. Renal oxygen delivery: matching delivery to metabolic demand. Clin. Exp. Pharmacol. Physiol. 33, 961–967 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Soltoff, S. P. ATP and the regulation of renal cell function. Annu. Rev. Physiol. 48, 9–31 (1986).

    Article  CAS  PubMed  Google Scholar 

  5. Holechek, M. J. et al. Glomerular filtration: an overview. Nephrol. Nurs. J. 30, 285–290, quiz 281–282 (2003).

    PubMed  Google Scholar 

  6. Dimmer, K. S. & Scorrano, L. (De)constructing mitochondria: what for? Physiol. (Bethesda) 21, 233–241 (2006).

    CAS  Google Scholar 

  7. Lodish, H. et al. in Molecular Cell Biology (W. H. Freeman and Company, 2000).

    Google Scholar 

  8. Weinberg, J. M. et al. Anaerobic and aerobic pathways for salvage of proximal tubules from hypoxia-induced mitochondrial injury. Am. J. Physiol. Renal Physiol. 279, F927–F943 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Pollak, M. R., Quaggin, S. E., Hoenig, M. P. & Dworkin, L. D. The glomerulus: the sphere of influence. Clin. J. Am. Soc. Nephrol. 9, 1461–1469 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chen, Y., Fry, B. C. & Layton, A. T. Modeling glucose metabolism and lactate production in the kidney. Math. Biosci. 289, 116–129 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gerich, J. E. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 27, 136–142 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Thomas, S. R. Inner medullary lactate production and accumulation: a vasa recta model. Am. J. Physiol. Renal Physiol. 279, F468–F481 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Ross, B. D., Espinal, J. & Silva, P. Glucose metabolism in renal tubular function. Kidney Int. 29, 54–67 (1986).

    Article  CAS  PubMed  Google Scholar 

  14. Scott, C. Misconceptions about aerobic and anaerobic energy expenditure. J. Int. Soc. Sports Nutr. 2, 32 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wirthensohn, G. & Guder, W. G. Renal substrate metabolism. Physiol. Rev. 66, 469–497 (1986).

    Article  CAS  PubMed  Google Scholar 

  16. Guder, W. G. & Ross, B. D. Enzyme distribution along the nephron. Kidney Int. 26, 101–111 (1984).

    Article  CAS  PubMed  Google Scholar 

  17. Lewy, P. R., Quintanilla, A., Levin, N. W. & Kessler, R. H. Renal energy metabolism and sodium reabsorption. Annu. Rev. Med. 24, 365–384 (1973).

    Article  CAS  PubMed  Google Scholar 

  18. Simon, N. & Hertig, A. Alteration of fatty acid oxidation in tubular epithelial cells: from acute kidney injury to renal fibrogenesis. Front. Med. (Lausanne) 2, 52 (2015). This review discusses the mechanisms behind fatty acid transport and oxidation in proximal tubules and how therapeutic agents restore β -oxidation in renal diseases.

    Google Scholar 

  19. Iwao, Y. et al. CD36 is one of important receptors promoting renal tubular injury by advanced oxidation protein products. Am. J. Physiol. Renal Physiol. 295, F1871–F1880 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Sabbahy, M. E. & Vaidya, V. S. Ischemic kidney injury and mechanisms of tissue repair. Wiley Interdiscip. Rev. Syst. Biol. Med. 3, 606–618 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Forbes, J. M. Mitochondria-power players in kidney function? Trends Endocrinol. Metab. 27, 441–442 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Bobulescu, I. A. Renal lipid metabolism and lipotoxicity. Curr. Opin. Nephrol. Hypertens. 19, 393–402 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Proctor, G. et al. Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and OVE26 mice with type 1 diabetes. Diabetes 55, 2502–2509 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Arici, M., Chana, R., Lewington, A., Brown, J. & Brunskill, N. J. Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-γ. J. Am. Soc. Nephrol. 14, 17–27 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Ruggiero, C. et al. Albumin-bound fatty acids but not albumin itself alter redox balance in tubular epithelial cells and induce a peroxide-mediated redox-sensitive apoptosis. Am. J. Physiol. Renal Physiol. 306, F896–F906 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gutteridge, J. M. C. & Halliwell, B. Invited review free radicals in disease processes: a compilation of cause and consequence. Free Radic. Res. Commun. 19, 141–158 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Ray, P. D., Huang, B. W. & Tsuji, Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 24, 981–990 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Holmstrom, K. M. & Finkel, T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat. Rev. Mol. Cell. Biol. 15, 411–421 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Ruiz, S. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic. Kidney Int. 83, 1029–1041 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weisiger, R. A. & Fridovich, I. Mitochondrial superoxide simutase. Site of synthesis and intramitochondrial localization. J. Biol. Chem. 248, 4793–4796 (1973).

    CAS  PubMed  Google Scholar 

  31. Teruya, R. et al. Expression of oxidative stress and antioxidant defense genes in the kidney of inbred mice after intestinal ischemia and reperfusion. Acta Cir. Bras. 28, 848–855 (2013).

    Article  PubMed  Google Scholar 

  32. Ribas, V., García-Ruiz, C. & Fernández-Checa, J. C. Glutathione and mitochondria. Front. Pharmacol. 5, 151 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lushchak, V. I. Glutathione homeostasis and functions: potential targets for medical interventions. J. Amino Acids 2012, 26 (2012).

    Article  CAS  Google Scholar 

  34. Handy, D. E. et al. Glutathione peroxidase-1 regulates mitochondrial function to modulate. J. Biol. Chem. 284, 11913–11921 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fedorenko, A., Lishko, P. V. & Kirichok, Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151, 400–413 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Brand, M. D. & Esteves, T. C. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab. 2, 85–93 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Brand, M. D. et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic. Biol. Med. 37, 755–767 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Zhou, Y. et al. UCP2 attenuates apoptosis of tubular epithelial cells in renal ischemia/reperfusion injury. Am. J. Physiol. Renal Physiol. http://dx.doi.org/10.1152/ajprenal.00118.2017 (2017). This study suggests a role for UCP2 in restoring tubular function after AKI by reducing tubular cell apoptosis.

  39. Souza, B. M. d. et al. Polymorphisms of the UCP2 gene are associated with glomerular filtration rate in type 2 diabetic patients and with decreased UCP2 gene expression in human kidney. PLoS ONE 10, e0132938 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Haase, V. H. Hypoxia-inducible factors in the kidney. Am. J. Physiol. Renal Physiol. 291, F271–F281 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Semenza, G. L. Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem. J. 405, 1–9 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Chandel, N. S. et al. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc. Natl Acad. Sci. USA 95, 11715–11720 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chandel, N. S. et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia: a mechanism of O2 sensing. J. Biol. Chem. 275, 25130–25138 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Klimova, T. & Chandel, N. S. Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ. 15, 660–666 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Fantus, D., Rogers, N. M., Grahammer, F., Huber, T. B. & Thomson, A. W. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat. Rev. Nephrol. 12, 587–609 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kim, Y. & Park, C. W. Adenosine monophosphate-activated protein kinase in diabetic nephropathy. Kidney Res. Clin. Pract. 35, 69–77 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Grahammer, F. et al. mTORC2 critically regulates renal potassium handling. J. Clin. Invest. 126, 1773–1782 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Gleason, C. E. et al. mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity. J. Clin.Invest. 125, 117–128 (2015).

    Article  PubMed  Google Scholar 

  50. Cunningham, J. T. et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1α transcriptional complex. Nature 450, 736–740 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Grahammer, F. et al. mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress. Proc. Natl Acad. Sci. USA 111, E2817–E2826 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hardie, D. G. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 25, 1895–1908 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mihaylova, M. M. & Shaw, R. J. The AMP-activated protein kinase (AMPK) signaling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13, 1016–1023 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Melser, S. et al. Rheb regulates mitophagy induced by mitochondrial energetic status. Cell Metab. 17, 719–730 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Scarpulla, R. C. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim. Biophys. Acta 1813, 1269–1278 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Scarpulla, R. C., Vega, R. B. & Kelly, D. P. Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol. Metab. 23, 459–466 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Svensson, K., Schnyder, S., Cardel, B. & Handschin, C. Loss of renal tubular PGC-1α exacerbates diet-induced renal steatosis and age-related urinary sodium excretion in mice. PLoS ONE 11, e0158716 (2016). This study shows the importance of PGC1 α in basic renal physiology, further supporting PGC1 α as a therapeutic target for renal diseases.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rasbach, K. A. & Schnellmann, R. G. PGC-1α over-expression promotes recovery from mitochondrial dysfunction and cell injury. Biochem. Biophys. Res. Commun. 355, 734–739 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Fan, W. & Evans, R. PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr. Opin. Cell Biol. 33, 49–54 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Huang, P., Chandra, V. & Rastinejad, F. Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu. Rev. Physiol. 72, 247–272 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vega, R. B., Huss, J. M. & Kelly, D. P. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor α in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol. Cell. Biol. 20, 1868–1876 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Huss, J. M., Kopp, R. P. & Kelly, D. P. Peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-α and -γ. Identification of novel leucine-rich interaction motif within PGC-1α. J. Biol. Chem. 277, 40265–40274 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Whitaker, R. M., Corum, D., Beeson, C. C. & Schnellmann, R. G. Mitochondrial biogenesis as a pharmacological target: A new approach to acute and chronic diseases. Annu. Rev. Pharmacol. Toxicol. 56, 229–249 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Fernandez-Marcos, P. J. & Auwerx, J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am. J. Clin. Nutr. 93, 884S–890S (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cameron, R. B., Beeson, C. C. & Schnellmann, R. G. Development of therapeutics that induce mitochondrial biogenesis for the treatment of acute and chronic degenerative diseases. J. Med. Chem. 59, 10411–10434 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Villena, J. A. New insights into PGC-1 coactivators: redefining their role in the regulation of mitochondrial function and beyond. FEBS J. 282, 647–672 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Finck, B. N. & Kelly, D. P. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J. Clin. Invest. 116, 615–622 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Palikaras, K. & Tavernarakis, N. Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp. Gerontol. 56, 182–188 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Lee, H. C. & Wei, Y. H. Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int. J. Biochem. Cell Biol. 37, 822–834 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Ahn, B. H. et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl Acad. Sci. USA 105, 14447–14452 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kong, X. et al. Sirtuin 3, a new target of PGC-1α, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS ONE http://dx.doi.org/10.1371/journal.pone.0011707 (2010).

  73. Handschin, C., Rhee, J., Lin, J., Tarr, P. T. & Spiegelman, B. M. An autoregulatory loop controls peroxisome proliferator-activated receptor γ coactivator 1α expression in muscle. Proc. Natl Acad. Sci. USA 100, 7111–7116 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Nisoli, E. et al. Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals. Proc. Natl Acad. Sci. USA 101, 16507–16512 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310, 314–317 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Whitaker, R. M., Wills, L. P., Stallons, L. J. & Schnellmann, R. G. cGMP-selective phosphodiesterase inhibitors stimulate mitochondrial biogenesis and promote recovery from acute kidney injury. J. Pharmacol. Exp. Ther. 347, 626–634 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lemasters, J. J. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuven. Res. 8, 3–5 (2005).

    Article  CAS  Google Scholar 

  78. Alexander, C. et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat. Genet. 26, 211–215 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Delettre, C. et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat. Genet. 26, 207–210 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Delettre, C., Lenaers, G., Pelloquin, L., Belenguer, P. & Hamel, C. P. OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease. Mol. Genet. Metab. 75, 97–107 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Labbe, K., Murley, A. & Nunnari, J. Determinants and functions of mitochondrial behavior. Annu. Rev. Cell Dev. Biol. 30, 357–391 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Chan, D. C. Fusion and fission: interlinked processes critical for mitochondrial health. Annu. Rev. Genet. 46, 265–287 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Waterham, H. R. et al. A lethal defect of mitochondrial and peroxisomal fission. N. Engl. J. Med. 356, 1736–1741 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Rossignol, R. et al. Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res. 64, 985–993 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Mishra, P., Carelli, V., Manfredi, G. & Chan, D. C. Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab. 19, 630–641 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lu, B. Mitochondrial dynamics and neurodegeneration. Curr. Neurol. Neurosci. Rep. 9, 212–219 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Song, M. & Dorn, G. W. II. Mitoconfusion: noncanonical functioning of dynamism factors in static mitochondria of the heart. Cell Metab. 21, 195–205 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ziegler, D. V., Wiley, C. D. & Velarde, M. C. Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging. Aging Cell 14, 1–7 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Yoon, Y. S. et al. Formation of elongated giant mitochondria in DFO-induced cellular senescence: involvement of enhanced fusion process through modulation of Fis1. J. Cell. Physiol. 209, 468–480 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Romanello, V. & Sandri, M. Mitochondrial quality control and muscle mass maintenance. Front. Physiol. http://dx.doi.org/10.3389/fphys.2015.00422 (2015).

  91. Mourier, A. et al. Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels. J. Cell Biol. 208, 429–442 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Shutt, T., Geoffrion, M., Milne, R. & McBride, H. M. The intracellular redox state is a core determinant of mitochondrial fusion. EMBO Rep. 13, 909–915 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Song, Z., Chen, H., Fiket, M., Alexander, C. & Chan, D. C. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J. Cell Biol. 178, 749–755 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Anand, R. et al. The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J. Cell Biol. 204, 919–929 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Frezza, C. et al. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126, 177–189 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Boissan, M. et al. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling. Science 344, 1510–1515 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mishra, P. & Chan, D. C. Metabolic regulation of mitochondrial dynamics. J. Cell Biol. 212, 379–387 (2016). This review summarizes recent studies and mechanisms that relate metabolism and mitochondrial energetics to mitochondrial dynamics.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Twig, G., Hyde, B. & Shirihai, O. S. Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim. Biophys. Acta 1777, 1092–1097 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Liesa, M. & Shirihai, O. S. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 17, 491–506 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mears, J. A. et al. Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nat. Struct. Mol. Biol. 18, 20–26 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Otera, H., Ishihara, N. & Mihara, K. New insights into the function and regulation of mitochondrial fission. Biochim. Biophys. Acta 1833, 1256–1268 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Loson, O. C. et al. The mitochondrial fission receptor MiD51 requires ADP as a cofactor. Structure 22, 367–377 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Richter, V. et al. Structural and functional analysis of MiD51, a dynamin receptor required for mitochondrial fission. J. Cell Biol. 204, 477–486 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. van der Bliek, A. M., Shen, Q. & Kawajiri, S. Mechanisms of mitochondrial fission and fusion. Cold Spring Harb. Perspect. Biol. http://dx.doi.org/10.1101/cshperspect.a011072 (2013).

  105. Chang, C. R. & Blackstone, C. Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann. NY Acad. Sci. 1201, 34–39 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Chang, C. R. & Blackstone, C. Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J. Biol. Chem. 282, 21583–21587 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Slupe, A. M. et al. A calcineurin docking motif (LXVP) in dynamin-related protein 1 contributes to mitochondrial fragmentation and ischemic neuronal injury. J. Biol. Chem. 288, 12353–12365 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Cereghetti, G. M. et al. Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc. Natl Acad. Sci. USA 105, 15803–15808 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Eiyama, A. & Okamoto, K. PINK1/Parkin-mediated mitophagy in mammalian cells. Curr. Opin. Cell Biol. 33, 95–101 (2015).

    Article  CAS  PubMed  Google Scholar 

  110. Greene, A. W. et al. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep. 13, 378–385 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Matsuda, N. et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 189, 211–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Okatsu, K. et al. Phosphorylated ubiquitin chain is the genuine Parkin receptor. J. Cell Biol. 209, 111–128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Vives-Bauza, C. et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl Acad. Sci. USA 107, 378–383 (2010).

    Article  CAS  PubMed  Google Scholar 

  115. Tanaka, A. et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J. Cell Biol. 191, 1367–1380 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell. Biol. 12, 9–14 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Randow, F. & Youle, R. J. Self and nonself: how autophagy targets mitochondria and bacteria. Cell Host Microbe 15, 403–411 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Sarraf, S. A. et al. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 496, 372–376 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Chan, N. C. et al. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum. Mol. Genet. 20, 1726–1737 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Groenewoud, M. J. & Zwartkruis, F. J. Rheb and mammalian target of rapamycin in mitochondrial homoeostasis. Open Biol. 3, 130185 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Toyama, E. Q. et al. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351, 275–281 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhang, C.-S. & Lin, S.-C. AMPK promotes autophagy by facilitating mitochondrial fission. Cell Metab. 23, 399–401 (2016). This study suggests a direct role for AMPK in mitophagy by phosphorylating MFF, a mitophagy receptor on the outer mitochondrial membrane, to initiate fission and therefore mitophagy.

    Article  CAS  PubMed  Google Scholar 

  124. Chen, G. et al. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol. Cell 54, 362–377 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Liu, L. et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat. Cell Biol. 14, 177–185 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Novak, I. et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 11, 45–51 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Zhang, J. & Ney, P. A. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ. 16, 939–946 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Thomas, R. L., Kubli, D. A. & Gustafsson, A. B. Bnip3-mediated defects in oxidative phosphorylation promote mitophagy. Autophagy 7, 775–777 (2011).

    Article  PubMed  Google Scholar 

  129. Hanna, R. A. et al. Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. J. Biol. Chem. 287, 19094–19104 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kanki, T. Nix, a receptor protein for mitophagy in mammals. Autophagy 6, 433–435 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Scherz-Shouval, R. & Elazar, Z. Regulation of autophagy by ROS: physiology and pathology. Trends Biochem. Sci. 36, 30–38 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Li, Y. et al. Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb. J. Biol. Chem. 282, 35803–35813 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Maiuri, M. C. et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J. 26, 2527–2539 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ishihara, M. et al. Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury. Am. J. Physiol. Renal Physiol. 305, F495–F509 (2013).

    CAS  PubMed  Google Scholar 

  135. Tang, C., He, L., Liu, J. & Dong, Z. Mitophagy: Basic Mechanism and Potential Role in Kidney Diseases. Kidney Diseases 1, 71–79 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Che, R., Yuan, Y., Huang, S. & Zhang, A. Mitochondrial dysfunction in the pathophysiology of renal diseases. Am. J. Physiol. - Renal Physiol. 306, F367–F378 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Yang, Y. et al. Renoprotective approaches and strategies in acute kidney injury. Pharmacol. Ther. 163, 58–73 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Shusterman, N. et al. Risk factors and outcome of hospital-acquired acute renal failure. Clinical epidemiologic study. Am. J. Med. 83, 65–71 (1987).

    Article  CAS  PubMed  Google Scholar 

  139. Thadhani, R., Pascual, M. & Bonventre, J. V. Acute renal failure. N. Engl. J. Med. 334, 1448–1460 (1996).

    Article  CAS  PubMed  Google Scholar 

  140. Kelly, K. J. & Molitoris, B. A. Acute renal failure in the new millennium: time to consider combination therapy. Semin. Nephrol. 20, 4–19 (2000).

    CAS  PubMed  Google Scholar 

  141. Murugan, R. & Kellum, J. A. Acute kidney injury: what's the prognosis? Nat. Rev. Nephrol. 7, 209–217 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Waikar, S. S., Liu, K. D. & Chertow, G. M. Diagnosis, epidemiology and outcomes of acute kidney injury. Clin. J. Am. Soc. Nephrol. 3, 844–861 (2008).

    Article  PubMed  Google Scholar 

  143. Doyle, J. F. & Forni, L. G. Acute kidney injury: short-term and long-term effects. Crit. Care 20, 188 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Hsu, C. & Liu, K. D. Cardiovascular events after AKI: a new dimension. J. Am. Soc. Nephrol. 25, 425–427 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Selewski, D. T. & Symons, J. M. Acute kidney injury. Pediatr. Rev. 35, 30–41 (2014).

    Article  PubMed  Google Scholar 

  146. Paraskevas, K. I. & Mikhailidis, D. P. Contrast-induced acute kidney injury in patients undergoing carotid artery stenting: an underestimated issue. Angiology http://dx.doi.org/10.1177/0003319716668934 (2016).

  147. Schefold, J. C., Filippatos, G., Hasenfuss, G., Anker, S. D. & von Haehling, S. Heart failure and kidney dysfunction: epidemiology, mechanisms and management. Nat. Rev. Nephrol. 12, 610–623 (2016).

    Article  CAS  PubMed  Google Scholar 

  148. Basile, D. P., Anderson, M. D. & Sutton, T. A. Pathophysiology of acute kidney injury. Compr. Physiol. 2, 1303–1353 (2012).

    PubMed  PubMed Central  Google Scholar 

  149. Ishimoto, Y. & Inagi, R. Mitochondria: a therapeutic target in acute kidney injury. Nephrol. Dial. Transplant. 31, 1062–1069 (2016).

    Article  CAS  PubMed  Google Scholar 

  150. Emma, F., Montini, G., Parikh, S. M. & Salviati, L. Mitochondrial dysfunction in inherited renal disease and acute kidney injury. Nat. Rev. Nephrol. 12, 267–280 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Funk, J. A. & Schnellmann, R. G. Persistent disruption of mitochondrial homeostasis after acute kidney injury. Am. J. Physiol. Renal Physiol. 302, F853–F864 (2012).

    Article  PubMed  Google Scholar 

  152. Tran, M. et al. PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice. J. Clin. Invest. 121, 4003–4014 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Parikh, S. M. Therapeutic targeting of the mitochondrial dysfunction in septic acute kidney injury. Curr. Opin. Crit. Care 19, 554–559 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Ruidera, E. et al. Fatty acid metabolism in renal ischemia. Lipids 23, 882–884 (1988).

    Article  CAS  PubMed  Google Scholar 

  155. Johnson, A. C., Stahl, A. & Zager, R. A. Triglyceride accumulation in injured renal tubular cells: alterations in both synthetic and catabolic pathways. Kidney Int. 67, 2196–2209 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Zager, R. A., Johnson, A. C. & Hanson, S. Y. Renal tubular triglyercide accumulation following endotoxic, toxic, and ischemic injury. Kidney Int. 67, 111–121 (2005).

    Article  CAS  PubMed  Google Scholar 

  157. Portilla, D. Role of fatty acid beta-oxidation and calcium-independent phospholipase A2 in ischemic acute renal failure. Curr. Opin. Nephrol. Hypertens. 8, 473–477 (1999).

    Article  CAS  PubMed  Google Scholar 

  158. Idrovo, J. P., Yang, W. L., Nicastro, J., Coppa, G. F. & Wang, P. Stimulation of carnitine palmitoyltransferase 1 improves renal function and attenuates tissue damage after ischemia/reperfusion. J. Surg. Res. 177, 157–164 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Smith, J. A., Stallons, L. J. & Schnellmann, R. G. Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury. Am. J. Physiol. Renal Physiol. 307, F435–F444 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zager, R. A., Johnson, A. C. & Becker, K. Renal cortical pyruvate depletion during AKI. J. Am. Soc. Nephrol. 25, 998–1012 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Lan, R. et al. Mitochondrial pathology and glycolytic shift during proximal tubule atrophy after ischemic AKI. J. Am. Soc. Nephrol. 27, 3356–3367 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Venkatachalam, M. A., Weinberg, J. M., Kriz, W. & Bidani, A. K. Failed tubule recovery, AKI-CKD transition, and kidney disease progression. J. Am. Soc. Nephrol. 26, 1765–1776 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Eklund, T., Wahlberg, J., Ungerstedt, U. & Hillered, L. Interstitial lactate, inosine and hypoxanthine in rat kidney during normothermic ischaemia and recirculation. Acta Physiol. Scand. 143, 279–286 (1991).

    Article  CAS  PubMed  Google Scholar 

  164. Zhan, M., Brooks, C., Liu, F., Sun, L. & Dong, Z. Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology. Kidney Int. 83, 568–581 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Brooks, C., Wei, Q., Cho, S. G. & Dong, Z. Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J. Clin. Invest. 119, 1275–1285 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Cho, S. G., Du, Q., Huang, S. & Dong, Z. Drp1 dephosphorylation in ATP depletion-induced mitochondrial injury and tubular cell apoptosis. Am. J. Physiol. Renal Physiol. 299, F199–F206 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Jiang, M. et al. Autophagy in proximal tubules protects against acute kidney injury. Kidney Int. 82, 1271–1283 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Liu, S. et al. Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy 8, 826–837 (2012).

    Article  CAS  PubMed  Google Scholar 

  169. Kimura, T. et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J. Am. Soc. Nephrol. 22, 902–913 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Duann, P., Lianos, E. A., Ma, J. & Lin, P. H. Autophagy, innate immunity and tissue repair in acute kidney injury. Int. J. Mol. Sci. 17, 662 (2016).

    Article  CAS  PubMed Central  Google Scholar 

  171. Wei, Q., Dong, G., Chen, J. K., Ramesh, G. & Dong, Z. Bax and Bak have critical roles in ischemic acute kidney injury in global and proximal tubule-specific knockout mouse models. Kidney Int. 84, 138–148 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Stallons, L. J., Whitaker, R. M. & Schnellmann, R. G. Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis. Toxicol. Lett. 224, 326–332 (2014).

    Article  CAS  PubMed  Google Scholar 

  173. Tran, M. T. et al. PGC1α-dependent NAD biosynthesis links oxidative metabolism to renal protection. Nature 531, 528–532 (2016). This investigation shows the importance of NAD biosynthesis in the recovery phase of AKI and of PGC1 α as an important regulator of NAD biosynthesis, highlighting this pathway as a therapeutic target for AKI.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Jesinkey, S. R. et al. Formoterol restores mitochondrial and renal function after ischemia-reperfusion injury. J. Am. Soc. Nephrol. 25, 1157–1162 (2014). This study provides the first proof of principle that stimulation of mitochondrial biogenesis after AKI can restore mitochondrial function and renal function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Garrett, S. M., Whitaker, R. M., Beeson, C. C. & Schnellmann, R. G. Agonism of the 5-hydroxytryptamine 1F receptor promotes mitochondrial biogenesis and recovery from acute kidney injury. J. Pharmacol. Exp. Ther. 350, 257–264 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Perico, L., Morigi, M. & Benigni, A. Mitochondrial sirtuin 3 and renal diseases. Nephron 134, 14–19 (2016).

    Article  CAS  PubMed  Google Scholar 

  177. Maahs, D. M. & Rewers, M. Mortality and renal disease in type 1 diabetes mellitus—progress made, more to be done. J. Clin. Endocrinol. Metab. 91, 3757–3759 (2006).

    Article  CAS  PubMed  Google Scholar 

  178. Collins, A. J. et al. US Renal Data System 2011 annual data report. Am. J. Kidney Dis. 59, A7 (2012).

    Article  PubMed  Google Scholar 

  179. Miranda-Diaz, A. G., Pazarin-Villasenor, L., Yanowsky-Escatell, F. G. & Andrade-Sierra, J. Oxidative stress in diabetic nephropathy with early chronic kidney disease. J. Diabetes Res. 2016, 7047238 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Flemming, N. B., Gallo, L. A., Ward, M. S. & Forbes, J. M. Tapping into mitochondria to find novel targets for diabetes complications. Curr. Drug Targets 17, 1341–1349 (2016). This review summarizes the role of mitochondrial ROS production in diabetes, which is a controversial contributor to the development and progression of diabetes.

    Article  CAS  PubMed  Google Scholar 

  181. Coughlan, M. T. et al. Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes. Clin. Sci. (Lond.) 130, 711–720 (2016). This study showed that diabetes-induced changes in mitochondrial morphology and energetics occur prior to renal lesions, suggesting that mitochondrial dysfunction is a primary cause of diabetes rather than a contributor.

    Article  CAS  Google Scholar 

  182. Higgins, G. C. & Coughlan, M. T. Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy? Br. J. Pharmacol. 171, 1917–1942 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Coughlan, M. T. & Sharma, K. Challenging the dogma of mitochondrial reactive oxygen species overproduction in diabetic kidney disease. Kidney Int. 90, 272–279 (2016).

    Article  CAS  PubMed  Google Scholar 

  184. Giacco, F. & Brownlee, M. Oxidative stress and diabetic complications. Circ. Res. 107, 1058–1070 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

    Article  CAS  PubMed  Google Scholar 

  186. Lonn, E. et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293, 1338–1347 (2005).

    Article  PubMed  Google Scholar 

  187. Hallan, S. & Sharma, K. The role of mitochondria in diabetic kidney disease. Curr. Diab. Rep. 16, 61 (2016).

    Article  CAS  PubMed  Google Scholar 

  188. Burch, H. B. et al. Metabolic effects of large fructose loads in different parts of the rat nephron. J. Biol. Chem. 255, 8239–8244 (1980).

    CAS  PubMed  Google Scholar 

  189. Lanaspa, M. A. et al. Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. J. Am. Soc. Nephrol. 25, 2526–2538 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Diggle, C. P. et al. Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme. J. Histochem. Cytochem. 57, 763–774 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Wai, T. & Langer, T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol. Metab. 27, 105–117 (2016).

    Article  CAS  PubMed  Google Scholar 

  192. Wang, W. et al. Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab. 15, 186–200 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Tang, W. X., Wu, W. H., Zeng, X. X., Bo, H. & Huang, S. M. Early protective effect of mitofusion 2 overexpression in STZ-induced diabetic rat kidney. Endocr 41, 236–247 (2012).

    Article  CAS  Google Scholar 

  194. Hickey, F. B. et al. IHG-1 increases mitochondrial fusion and bioenergetic function. Diabetes 63, 4314–4325 (2014).

    Article  CAS  PubMed  Google Scholar 

  195. Hickey, F. B. et al. IHG-1 promotes mitochondrial biogenesis by stabilizing PGC-1α. J. Am. Soc. Nephrol. 22, 1475–1485 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Guo, K. et al. Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling. PLoS ONE 10, e0125176 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Imasawa, T. et al. High glucose repatterns human podocyte energy metabolism during differentiation and diabetic nephropathy. FASEB J. 31, 294–307 (2017).

    Article  CAS  PubMed  Google Scholar 

  198. Qi, W. et al. Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction. Nat. Med. 23, 753–762 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Szeto, H. H. et al. Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury. Kidney Int. 90, 997–1011 (2016).

    Article  CAS  PubMed  Google Scholar 

  200. Lempiainen, J., Finckenberg, P., Levijoki, J. & Mervaala, E. AMPK activator AICAR ameliorates ischaemia reperfusion injury in the rat kidney. Br. J. Pharmacol. 166, 1905–1915 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Ruderman, N. B., Carling, D., Prentki, M. & Cacicedo, J. M. AMPK, insulin resistance, and the metabolic syndrome. J. Clin. Invest. 123, 2764–2772 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Dugan, L. L. et al. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J. Clin. Invest. 123, 4888–4899 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Pillai, V. B. et al. Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J. Biol. Chem. 285, 3133–3144 (2010).

    Article  CAS  PubMed  Google Scholar 

  204. Palacios, O. M. et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1α in skeletal muscle. Aging (Albany NY) 1, 771–783 (2009).

    Article  CAS  Google Scholar 

  205. Nogueiras, R. et al. Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol. Rev. 92, 1479–1514 (2012)

    Article  CAS  PubMed  Google Scholar 

  206. Morigi, M. et al. Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury. J. Clin. Invest. 125, 715–726 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Singh, J. P., Singh, A. P. & Bhatti, R. Explicit role of peroxisome proliferator-activated receptor γ in gallic acid-mediated protection against ischemia-reperfusion-induced acute kidney injury in rats. J. Surg. Res. 187, 631–639 (2014).

    Article  CAS  PubMed  Google Scholar 

  208. Chung, B. H. et al. Protective effect of peroxisome proliferator activated receptor γ agonists on diabetic and non-diabetic renal diseases. Nephrol. (Carlton, Vic.) 10 (Suppl.), S40–S43 (2005).

    Article  CAS  Google Scholar 

  209. Sivarajah, A. et al. Agonists of peroxisome-proliferator activated receptor-γ reduce renal ischemia/reperfusion injury. Am. J. Nephrol. 23, 267–276 (2003).

    Article  CAS  PubMed  Google Scholar 

  210. Staels, B. et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 98, 2088–2093 (1998).

    Article  CAS  PubMed  Google Scholar 

  211. Wu, Q. Q. et al. Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1. Am. J. Physiol. Renal Physiol. 300, F1180–F1192 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. de Zeeuw, D. et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med. 369, 2492–2503 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Park, C. W. et al. PPARα agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int. 69, 1511–1517 (2006).

    Article  CAS  PubMed  Google Scholar 

  214. Stadler, K., Goldberg, I. J. & Susztak, K. The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease. Curr. Diabetes Rep. 15, 40 (2015).

    Article  CAS  Google Scholar 

  215. Al-Rasheed, N. M. et al. Fenofibrate attenuates diabetic nephropathy in experimental diabetic rat's model via suppression of augmented TGF-β1/Smad3 signaling pathway. Arch. Physiol. Biochem. 122, 186–194 (2016).

    Article  CAS  PubMed  Google Scholar 

  216. Hong, Y. A. et al. Fenofibrate improves renal lipotoxicity through activation of AMPK-PGC-1α in db/db mice. PLoS ONE 9, e96147 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Kawanami, D., Matoba, K. & Utsunomiya, K. Dyslipidemia in diabetic nephropathy. Ren. Replace. Ther. 2, 16 (2016).

    Article  Google Scholar 

  218. Szeto, H. H. & Birk, A. V. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin. Pharmacol. Ther. 96, 672–683 (2014). The Szeto peptides described in this study are novel, as they prevent the peroxidation of cardiolipin and therefore preserve mitochondrial function, demonstrating that they are renoprotective.

    Article  CAS  PubMed  Google Scholar 

  219. Hanske, J. et al. Conformational properties of cardiolipin-bound cytochrome c. Proc. Natl Acad. Sci. USA 109, 125–130 (2012).

    Article  CAS  PubMed  Google Scholar 

  220. Basova, L. V. et al. Cardiolipin switch in mitochondria: shutting off the reduction of cytochrome c and turning on the peroxidase activity. Biochemistry 46, 3423–3434 (2007).

    Article  CAS  PubMed  Google Scholar 

  221. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02436447 (2015).

  222. Sedeek, M., Nasrallah, R., Touyz, R. M. & Hebert, R. L. NADPH oxidases, reactive oxygen species, and the kidney: friend and foe. J. Am. Soc. Nephrol. 24, 1512–1518 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Bai, J. & Cederbaum, A. I. Mitochondrial catalase and oxidative injury. Biol. Signals Recept. 10, 189–199 (2001).

    Article  CAS  PubMed  Google Scholar 

  224. Scarpulla, R. C. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev. 88, 611–638 (2008).

    Article  CAS  PubMed  Google Scholar 

  225. Kaufman, B. A. et al. The mitochondrial transcription factor TFAM coordinates the assembly of multiple DNA molecules into nucleoid-like structures. Mol. Biol. Cell 18, 3225–3236 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Virbasius, J. V. & Scarpulla, R. C. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc. Natl Acad. Sci. USA 91, 1309–1313 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).

    Article  CAS  PubMed  Google Scholar 

  228. Halseth, A. E., Ensor, N. J., White, T. A., Ross, S. A. & Gulve, E. A. Acute and chronic treatment of ob/ob and db/db mice with AICAR decreases blood glucose concentrations. Biochem. Biophys. Res. Commun. 294, 798–805 (2002).

    Article  CAS  PubMed  Google Scholar 

  229. Keech, A. et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366, 1849–1861 (2005).

    Article  CAS  PubMed  Google Scholar 

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    Pallavi Bhargava & Rick G. Schnellmann

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Glossary

Carnitine shuttle

Enzymes in the mitochondrial membrane that transport long-chain fatty acids from the cytosol to the mitochondrial matrix by replacing their coA group with carnitine.

Mitochondrial cristae

Folds in the mitochondrial inner membrane that increase the surface area for mitochondrial respiration to take place.

Streptozotocin

A glucosamine-nitrosourea that is used to induce experimental diabetes in animals by specifically targeting and damaging beta cells.

Dyslipidaemia

Abnormalities in lipoprotein metabolism, resulting in elevated or deficient levels of lipids and/or lipoproteins in the body.

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Bhargava, P., Schnellmann, R. Mitochondrial energetics in the kidney. Nat Rev Nephrol 13, 629–646 (2017). https://doi.org/10.1038/nrneph.2017.107

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