Review Article | Published:

Mitochondrial dysfunction in diabetic kidney disease

Nature Reviews Nephrology volume 14, pages 291312 (2018) | Download Citation

Abstract

Globally, diabetes is the leading cause of chronic kidney disease and end-stage renal disease, which are major risk factors for cardiovascular disease and death. Despite this burden, the factors that precipitate the development and progression of diabetic kidney disease (DKD) remain to be fully elucidated. Mitochondrial dysfunction is associated with kidney disease in nondiabetic contexts, and increasing evidence suggests that dysfunctional renal mitochondria are pathological mediators of DKD. These complex organelles have a broad range of functions, including the generation of ATP. The kidneys are mitochondrially rich, highly metabolic organs that require vast amounts of ATP for their normal function. The delivery of metabolic substrates for ATP production, such as fatty acids and oxygen, is altered by diabetes. Changes in metabolic fuel sources in diabetes to meet ATP demands result in increased oxygen consumption, which contributes to renal hypoxia. Inherited factors including mutations in genes that impact mitochondrial function and/or substrate delivery may also be important risk factors for DKD. Hence, we postulate that the diabetic milieu and inherited factors that underlie abnormalities in mitochondrial function synergistically drive the development and progression of DKD.

Key points

  • The kidneys are highly metabolic organs, and their function is tightly coupled to mitochondrial energy production

  • Kidneys share their reliance on mitochondrial energy production with other organs that are similarly susceptible to diabetes complications, such as the heart and nervous system

  • Dysfunctional mitochondria are present in nondiabetic kidney disease and in diabetic kidneys; defects include impaired respiratory chain function, structural and networking abnormalities, disrupted cellular signalling and increased reactive oxygen species generation

  • Diabetes alters the delivery of substrates and oxygen to the kidneys and results in switching to alternative substrates for ATP production to meet increased energy requirements, including a shift towards glucose oxidation in the proximal tubules

  • Mitochondrial fission and fusion events enable energy demands to be met and provide mitochondrial quality control; disruption of these events in diabetes prevents elimination of damaged mitochondria and exacerbates ATP deficits

  • Evidence from preclinical models suggests that mitochondrial damage in diabetes can be pharmacologically repaired to improve kidney function; several potential therapies are currently in clinical trials for mitochondriopathies and/or chronic kidney disease

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.

References

  1. 1.

    , , , & Estimating the current and future costs of Type 1 and Type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabet. Med. 29, 855–862 (2012). This article highlights the morbidity, mortality and economic costs of DKD.

  2. 2.

    in International Textbook of Diabetes Mellitus (eds DeFronzo, R. A., Ferrannini, E., Zimmet, P. & Alberti, G. M. M.) 1113–1124 (John WIley & Sons, West Sussex, UK, 2015).

  3. 3.

    et al. The systemic nature of CKD. Nat. Rev. Nephrol. 13, 344–358 (2017).

  4. 4.

    & Mechanisms of diabetic complications. Physiol. Rev. 93, 137–188 (2013).

  5. 5.

    , , & Molecular mechanisms of diabetic kidney disease. J. Clin. Invest. 124, 2333–2340 (2014).

  6. 6.

    et al. Prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, United States, 1980–2012. JAMA 312, 1218–1226 (2014).

  7. 7.

    et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care 37, 2864–2883 (2014).

  8. 8.

    , , & Chronic kidney disease in the general population. Adv Chron. Kidney Dis. 12, 5–13 (2005).

  9. 9.

    , , , & Mortality rates in trials of subjects with type 2 diabetes. J. Am. Heart Assoc. 1, 8–15 (2012).

  10. 10.

    et al. Microalbuminuria prevalence varies with age, sex, and puberty in children with type 1 diabetes followed from diagnosis in a longitudinal study. Oxford Regional Prospective Study Group. Diabetes Care 22, 495–502 (1999). This research shows that kidney disease in diabetes begins much earlier than once thought and initiation does not require comorbidities such as hypertension or dyslipidaemia.

  11. 11.

    , , , & Association between obesity and kidney disease: a systematic review and meta-analysis. Kidney Int. 73, 19–33 (2008).

  12. 12.

    et al. The pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of 488 cases of diabetic glomerulosclerosis. Pathol. Res. Pract. 187, 251–259 (1991).

  13. 13.

    et al. Structural-functional relationships in diabetic nephropathy. J. Clin. Invest. 74, 1143–1155 (1984).

  14. 14.

    The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615–1625 (2005).

  15. 15.

    , , & Role of mitochondria-associated endoplasmic reticulum membrane in inflammation-mediated metabolic diseases. Mediators Inflamm. 2016, 1851420 (2016).

  16. 16.

    , , & Mitochondrial dysfunction in inherited renal disease and acute kidney injury. Nat. Rev. Nephrol. 12, 267–280 (2016).

  17. 17.

    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). This research demonstrates the high resting metabolic rate of the kidneys as compared with other organs.

  18. 18.

    , & Na-K-ATPase activity along the rabbit, rat, and mouse nephron. Am. J. Physiol. 237, F114–F120 (1979).

  19. 19.

    Metabolic substrates, cellular energy production, and the regulation of proximal tubular transport. Annu. Rev. Physiol. 47, 85–101 (1985).

  20. 20.

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

  21. 21.

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

  22. 22.

    et al. Molecular cloning of a cDNA for a human ADP/ATP carrier which is growth-regulated. J. Biol. Chem. 262, 4355–4359 (1987).

  23. 23.

    et al. Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature 426, 39–44 (2003).

  24. 24.

    Distribution and function of classes of ATPases along the nephron. Kidney Int. 29, 21–31 (1986).

  25. 25.

    The molecular machinery of Keilin's respiratory chain. Biochem. Soc. Trans. 31, 1095–1105 (2003).

  26. 26.

    & Brenner & Rector's The Kidney (Saunders, Philadelphia, PA, 2008).

  27. 27.

    & Stoichiometry and coupling of active transport to oxidative metabolism in epithelial tissues. Am. J. Physiol. 240, F357–F371 (1981). This research demonstrates the integral relationship that exists between renal solute transport and oxygen-dependent ATP production in the kidneys.

  28. 28.

    , & Sodium transport and oxygen consumption in the mammalian kidney. Nature 190, 919–921 (1961).

  29. 29.

    , , & Intrarenal oxygenation: unique challenges and the biophysical basis of homeostasis. Am. J. Physiol. Renal Physiol. 295, F1259–1270 (2008).

  30. 30.

    , & Determination of Na-K-ATPase activity in single segments of the mammalian nephron. Am. J. Physiol. 237, F105–F113 (1979). This paper shows the expression of mitochondrial coupled Na+/K+ ATPase in the nephron and how this is coupled to solute transport needs on the basis of the location.

  31. 31.

    , , & Multiphoton imaging reveals differences in mitochondrial function between nephron segments. J. Am. Soc. Nephrol. 20, 1293–1302 (2009).

  32. 32.

    & Quantitative morphology ofthe rat kidney. Int. J. Biochem. 12, 17–22 (1980).

  33. 33.

    & Renal gluconeogenesis. 2. The gluconeogenic capacity of the kidney cortex of various species. Biochem. J. 89, 398–400 (1963).

  34. 34.

    & The synthesis of glucose by the kidney. Bull. Johns Hopkins Hosp. 103, 77–93 (1958).

  35. 35.

    , , & Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 24, 382–391 (2001). This article provides an excellent overview of renal gluconeogenesis and how it contributes to systemic glucose homeostasis.

  36. 36.

    et al. Renal net glucose release in vivo and its contribution to blood glucose in rats. J. Clin. Invest. 62, 721–726 (1978).

  37. 37.

    et al. Renal substrate exchange and gluconeogenesis in normal postabsorptive humans. Am. J. Physiol. Endocrinol. Metab. 282, E428–E434 (2002).

  38. 38.

    et al. Relative importance of liver, kidney, and substrates in epinephrine-induced increased gluconeogenesis in humans. Am. J. Physiol. Endocrinol. Metab. 285, E819–E826 (2003).

  39. 39.

    et al. Regulation of gluconeogenesis by glutamine in normal postabsorptive humans. Am. J. Physiol. 272, E437–E445 (1997).

  40. 40.

    et al. Renal blood flow: measurement in vivo with rapid spiral MR imaging. Radiology 208, 729–734 (1998).

  41. 41.

    et al. Normal renal blood flow measurement using phase-contrast cine magnetic resonance imaging. Invest. Radiol 27, 465–470 (1992).

  42. 42.

    , & Tissue weights and rates of blood flow in man for the prediction of anesthetic uptake and distribution. Anesthesiology 35, 523–526 (1971).

  43. 43.

    , , & Studies on the circulation of an organ: simultaneous determination of coronary, cerebral and renal blood flow, of cardiac output and of the oxygen consumption of the heart, brain and kidneys [Italian]. Boll. Soc. Ital. Biol. Sper 36, 952–954 (1960).

  44. 44.

    , & Energy metabolism in surgical patients: oxygen consumption and blood flow. J. Surg. Res. 10, 613–627 (1970).

  45. 45.

    & Reference values for resting blood flow to organs of man. Clin. Phys. Physiol. Meas. 10, 187–217 (1989).

  46. 46.

    , & Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int. 84, 457–467 (2013).

  47. 47.

    , & Renal autoregulation in health and disease. Physiol. Rev. 95, 405–511 (2015).

  48. 48.

    , , , & Quantitative imaging of basic functions in renal (patho)physiology. Am. J. Physiol. Renal Physiol. 291, F495–F502 (2006).

  49. 49.

    Multiphoton imaging of renal tissues in vitro. Am. J. Physiol. Renal Physiol. 288, F1079–F1083 (2005).

  50. 50.

    Oxygen and renal metabolism. Kidney Int. 51, 381–385 (1997).

  51. 51.

    The proximal tubule in the pathophysiology of the diabetic kidney. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, R1009–R1022 (2011). This paper provides an overview of the tubular hypothesis of DKD.

  52. 52.

    , , , & Relation between renal interstitial ATP concentrations and autoregulation-mediated changes in renal vascular resistance. Circ. Res. 86, 656–662 (2000).

  53. 53.

    , , 3rd, & Renal interstitial atp responses to changes in arterial pressure during alterations in tubuloglomerular feedback activity. Hypertension 37, 753–759 (2001).

  54. 54.

    , & Effect of renal interstitial adenosine infusion on phosphate excretion in diabetes mellitus rats. Am. J. Physiol. 274, R1228–R1235 (1998).

  55. 55.

    , , , & Inhibition of sodium-linked glucose reabsorption normalizes diabetes-induced glomerular hyperfiltration in conscious adenosine A(1)-receptor deficient mice. Acta Physiol. 210, 440–445 (2014).

  56. 56.

    et al. Adenosine A(1) receptors determine glomerular hyperfiltration and the salt paradox in early streptozotocin diabetes mellitus. Nephron Physiol. 111, 30–38 (2009).

  57. 57.

    Proximal tubulopathy: prime mover and key therapeutic target in diabetic kidney disease. Diabetes 66, 791–800 (2017).

  58. 58.

    , , , & Glomerular hyperfiltration in type 1 diabetes mellitus results from primary changes in proximal tubular sodium handling without changes in volume expansion. Eur. J. Clin. Invest. 35, 330–336 (2005).

  59. 59.

    et al. Podocyte loss and progressive glomerular injury in type II diabetes. J. Clin. Invest. 99, 342–348 (1997).

  60. 60.

    et al. Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury. J. Clin. Invest. 126, 3336–3350 (2016).

  61. 61.

    et al. Glomerular endothelial mitochondrial dysfunction is essential and characteristic of diabetic kidney disease susceptibility. Diabetes 66, 763–778 (2017).

  62. 62.

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

  63. 63.

    et al. Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes. Clin. Sci. 130, 711–720 (2016). This article provides a time course of mitochondrial dysfunction in the diabetic kidney.

  64. 64.

    , , , & Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim. Biophys. Acta 1777, 935–940 (2008).

  65. 65.

    , , & Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension. Clin. Exp. Pharmacol. Physiol. 40, 123–137 (2013). This work highlights how oxygen is used by the diabetic kidney and how this may lead to hypoxia.

  66. 66.

    et al. Increased mitochondrial activity in renal proximal tubule cells from young spontaneously hypertensive rats. Kidney Int. 85, 561–569 (2014).

  67. 67.

    et al. Impact of high glucose and transforming growth factor-beta on bioenergetic profiles in podocytes. Metabolism 61, 1073–1086 (2012).

  68. 68.

    et al. Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of HIF-1alpha expression and oxygen metabolism. Diabetes 60, 981–992 (2011).

  69. 69.

    , , , & Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice. Am. J. Physiol. Renal Physiol. 310, F807–F809 (2016).

  70. 70.

    et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N. Engl. J. Med. 361, 2019–2032 (2009).

  71. 71.

    et al. High altitude may alter oxygen availability and renal metabolism in diabetics as measured by hyperpolarized [1-(13)C]pyruvate magnetic resonance imaging. Kidney Int. 86, 67–74 (2014).

  72. 72.

    et al. Hyperbaric oxygen therapy reduces renal lactate production. Physiol Rep. 5, e13217 (2017).

  73. 73.

    & A forgotten chapter in the history of the renal circulation: the Josep Trueta and Homer Smith intellectual conflict. Am. J. Physiol. Renal Physiol. 309, F90–F97 (2015).

  74. 74.

    , & Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int. Suppl. 65, S74–78 (1998).

  75. 75.

    Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J. Am. Soc. Nephrol. 17, 17–25 (2006).

  76. 76.

    et al. The metabolic syndrome induces early changes in the swine renal medullary mitochondria. Transl Res. 184, 45–56.e9 (2017).

  77. 77.

    et al. Rho-kinase inhibition prevents the progression of diabetic nephropathy by downregulating hypoxia-inducible factor 1alpha. Kidney Int. 84, 545–554 (2013).

  78. 78.

    et al. HIF-1 mediates renal fibrosis in OVE26 type 1 diabetic mice. Diabetes 65, 1387–1397 (2016).

  79. 79.

    Progressive renal decline: the new paradigm of diabetic nephropathy in type 1 diabetes. Diabetes Care 38, 954–962 (2015).

  80. 80.

    et al. The impact of hyperfiltration on the diabetic kidney. Diabetes Metab. 41, 5–17 (2015).

  81. 81.

    et al. Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus. N. Engl. J. Med. 324, 1626–1632 (1991).

  82. 82.

    , , & Primary proximal tubule hyperreabsorption and impaired tubular transport counterregulation determine glomerular hyperfiltration in diabetes: a modeling analysis. Am. J. Physiol. Renal Physiol. 312, F819–F835 (2017).

  83. 83.

    et al. Kidney hypoxia, attributable to increased oxygen consumption, induces nephropathy independently of hyperglycemia and oxidative stress. Hypertension 62, 914–919 (2013). This work suggests that increases in oxygen demand alone are sufficient to cause kidney disease as seen in the diabetic kidney.

  84. 84.

    et al. Mass spectrometry imaging reveals elevated glomerular ATP/AMP in diabetes/obesity and identifies sphingomyelin as a possible mediator. EBioMedicine 7, 121–134 (2016).

  85. 85.

    et al. Deficiency in apoptosis inducing factor recapitulates chronic kidney disease via aberrant mitochondrial homeostasis. Diabetes 65, 1085–1098 (2016).

  86. 86.

    , & The dark side of extracellular ATP in kidney diseases. J. Am. Soc. Nephrol. 26, 1007–1016 (2015).

  87. 87.

    & Intrarenal purinergic signaling in the control of renal tubular transport. Annu. Rev. Physiol. 72, 377–393 (2010).

  88. 88.

    et al. Increased levels of adenosine and ecto 5′-nucleotidase (CD73) activity precede renal alterations in experimental diabetic rats. Biochem. Biophys. Res. Commun. 468, 354–359 (2015).

  89. 89.

    et al. Reduced adenosine uptake and its contribution to signaling that mediates profibrotic activation in renal tubular epithelial cells: implication in diabetic nephropathy. PLoS ONE 11, e0147430 (2016).

  90. 90.

    et al. Localization of P2X1 purinoceptors by autoradiography and immunohistochemistry in rat kidneys. Am. J. Physiol. 274, F799–F804 (1998).

  91. 91.

    & Involvement of P2 receptors in regulation of glomerular permeability to albumin by extracellular nucleotides of intra-/extra-glomerular origins. J. Physiol. Pharmacol. 67, 177–183 (2016).

  92. 92.

    et al. Extracellular purines' action on glomerular albumin permeability in isolated rat glomeruli: insights into the pathogenesis of albuminuria. Am. J. Physiol. Renal Physiol. 311, F103–F111 (2016).

  93. 93.

    et al. Diabetes-induced hyperfiltration in adenosine A(1)-receptor deficient mice lacking the tubuloglomerular feedback mechanism. Acta Physiol. 190, 253–259 (2007).

  94. 94.

    et al. RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J. Am. Soc. Nephrol. 20, 742–752 (2009). This work highlights the importance of mitochondrial abnormalities in the development of DKD.

  95. 95.

    et al. Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease. Antioxid. Redox Signal. 19, 331–343 (2013). This paper demonstrates that decreasing mitochondrial function via complex I is sufficient to cause kidney disease, which precedes cardiac abnormalities in the absence of diabetes.

  96. 96.

    et al. Disparate effects on renal and oxidative parameters following RAGE deletion, AGE accumulation inhibition, or dietary AGE control in experimental diabetic nephropathy. Am. J. Physiol. Renal Physiol. 298, F763–F770 (2010).

  97. 97.

    , , , & In vivo multiphoton imaging of mitochondrial structure and function during acute kidney injury. Kidney Int. 83, 72–83 (2013).

  98. 98.

    & The not so 'mighty chondrion': emergence of renal diseases due to mitochondrial dysfunction. Nephron Physiol. 105, 1–10 (2007). This review highlights renal syndromes that include mitochondrial defects.

  99. 99.

    , , , & Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J. Biol. Chem. 276, 2571–2575 (2001).

  100. 100.

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

  101. 101.

    Mitochondrial hormesis and diabetic complications. Diabetes 64, 663–672 (2015).

  102. 102.

    , & Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 57, 1446–1454 (2008).

  103. 103.

    et al. Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am. J. Physiol. Renal Physiol. 289, F420–F430 (2005).

  104. 104.

    & Mitochondrial derangement: possible initiator of microalbuminuria in NIDDM. J. Diabet. Compl. 5, 104–106 (1991). This paper provides the first description of mitochondrial structural abnormalities in DKD.

  105. 105.

    , & Mitochondrial enlargement and basement membrane thickening of renal proximal tubules, possible initiators of microalbuminuria in non-insulin-dependent diabetics (NIDDM). Acta Pathol. Jpn 42, 793–799 (1992).

  106. 106.

    & Mitochondrial protein acetylation regulates metabolism. Essays Biochem. 52, 23–35 (2012).

  107. 107.

    , & Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases. Nat. Rev. Nephrol. 13, 213–225 (2017).

  108. 108.

    , , & Protein carbamylation in kidney disease: pathogenesis and clinical implications. Am. J. Kidney Dis. 64, 793–803 (2014).

  109. 109.

    , , & Post-translational oxidative modification and inactivation of mitochondrial complex I in epileptogenesis. J. Neurosci. 32, 11250–11258 (2012).

  110. 110.

    & Posttranslational modification of differentially expressed mitochondrial proteins in the retina during early experimental autoimmune uveitis. Mol. Vis. 17, 1814–1821 (2011).

  111. 111.

    et al. Tissue-specific remodeling of the mitochondrial proteome in type 1 diabetic akita mice. Diabetes 58, 1986–1997 (2009). This conceptually interesting study describes mitochondrial changes in organs prone to diabetic complications.

  112. 112.

    et al. Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature 535, 561–565 (2016).

  113. 113.

    et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat. Commun. 7, 12948 (2016).

  114. 114.

    , & Sirtuin and metabolic kidney disease. Kidney Int. 88, 691–698 (2015).

  115. 115.

    & Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress. Biochem. Soc. Trans. 36, 1045–1050 (2008).

  116. 116.

    et al. Mitochondrial response to oxidative and nitrosative stress in early stages of diabetes. Mitochondrion 13, 835–840 (2013).

  117. 117.

    et al. Effects of diabetes on oxidative and nitrosative stress in kidney mitochondria from aged rats. J. Bioenerg. Biomembr. 46, 511–518 (2014).

  118. 118.

    , & Increased peripheral blood mitochondrial DNA in type 2 diabetic patients with nephropathy. Diabetes Res. Clin. Pract. 86, e22–24 (2009).

  119. 119.

    et al. Association between mitochondrial DNA copy number in peripheral blood and incident CKD in the atherosclerosis risk in communities study. J. Am. Soc. Nephrol. 27, 2467–2473 (2016).

  120. 120.

    et al. Altered mitochondrial function, mitochondrial DNA and reduced metabolic flexibility in patients with diabetic nephropathy. EBioMedicine 2, 499–512 (2015). This study examines mitochondrial function in patients with established DKD.

  121. 121.

    & Hyperglycemia induced damage to mitochondrial respiration in renal mesangial and tubular cells: implications for diabetic nephropathy. Redox Biol. 10, 100–107 (2016).

  122. 122.

    et al. Methods for defining distinct bioenergetic profiles in platelets, lymphocytes, monocytes, and neutrophils, and the oxidative burst from human blood. Lab. Invest. 93, 690–700 (2013).

  123. 123.

    et al. Differential gene expression in diabetic nephropathy in individuals with type 1 diabetes. J. Clin. Endocrinol. Metab. 100, E876–882 (2015).

  124. 124.

    et al. Diabetic nephropathy is associated with gene expression levels of oxidative phosphorylation and related pathways. Diabetes 55, 1826–1831 (2006). This article presents an early description of mitochondrial abnormalities in skin fibroblasts taken from individuals with DKD.

  125. 125.

    et al. Circulating modified metabolites and a risk of ESRD in patients with type 1 diabetes and chronic kidney disease. Diabetes Care 40, 383–390 (2017).

  126. 126.

    et al. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J. Am. Soc. Nephrol. 24, 1901–1912 (2013). This paper examines urinary metabolites as predictors of DKD in humans.

  127. 127.

    et al. GC/TOFMS analysis of metabolites in serum and urine reveals metabolic perturbation of TCA cycle in db/db mice involved in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 304, F1317–1324 (2013).

  128. 128.

    et al. (1)H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin. Am. J. Physiol. Renal Physiol. 300, F947–F956 (2011).

  129. 129.

    , , & AMP-activated protein kinase (AMPK) activation inhibits nuclear translocation of Smad4 in mesangial cells and diabetic kidneys. Am. J. Physiol. Renal Physiol. 308, F1167–F1177 (2015).

  130. 130.

    et al. Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications. JCI Insight 1, e86976 (2016). This article presents static tracer studies following administration of various labelled substrates in diabetic mice.

  131. 131.

    et al. Cardiac metabolism in mice: tracer method developments and in vivo application revealing profound metabolic inflexibility in diabetes. Am. J. Physiol. Endocrinol. Metab. 290, E870–E881 (2006). This is a dynamic steady-state study of metabolic substrate flux in the diabetic heart.

  132. 132.

    , & Metabolic activities of the isolated perfused rat kidney. Biochem. J. 103, 852–862 (1967).

  133. 133.

    , , & Coupling of active ion transport and aerobic respiratory rate in isolated renal tubules. Proc. Natl Acad. Sci. USA 77, 447–451 (1980).

  134. 134.

    & The respiratory chain and oxidative phosphorylation. Adv. Enzymol. Relat. Subj. Biochem. 17, 65–134 (1956).

  135. 135.

    , , & Increased renal metabolism in diabetes. Mechanism and functional implications. Diabetes 43, 629–633 (1994).

  136. 136.

    , , & Relation between Na-K-ATPase activity and respiratory rate in the rat kidney. Am. J. Physiol. 230, 1432–1438 (1976).

  137. 137.

    , & Carbohydrate and lipid metabolism of the renal tubule in diabetes mellitus. Eur. J. Clin. Chem. Clin. Biochem. 30, 669–674 (1992).

  138. 138.

    , & Metabolic fuels along the nephron: pathways and intracellular mechanisms of interaction. Kidney Int. 29, 41–45 (1986).

  139. 139.

    & Substrate specificity to maintain cellular ATP along the mouse nephron. Am. J. Physiol. 255, F977–983 (1988).

  140. 140.

    The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977–986 (1993).

  141. 141.

    UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352, 854–865 (1998).

  142. 142.

    , , , & Renal amino acid, fat and glucose metabolism in type 1 diabetic and non-diabetic humans: effects of acute insulin withdrawal. Diabetologia 49, 1901–1908 (2006).

  143. 143.

    et al. Insufficient insulin administration to diabetic rats increases substrate utilization and maintains lactate production in the kidney. Physiol. Rep. 2, e12233 (2014).

  144. 144.

    The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358, 2545–2559 (2008).

  145. 145.

    The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560–2572 (2008).

  146. 146.

    , , & Role of altered insulin signaling pathways in the pathogenesis of podocyte malfunction and microalbuminuria. Curr. Opin. Nephrol. Hypertens. 18, 539–545 (2009).

  147. 147.

    et al. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab. 12, 329–340 (2010).

  148. 148.

    The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu. Rev. Med. 66, 255–270 (2015).

  149. 149.

    et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 375, 323–334 (2016). This article presents the phase III clinical trial of SGLT2 inhibition in DKD, showing efficacy that was not necessarily dependent on the glucose-lowering effects of this class of drug.

  150. 150.

    et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015).

  151. 151.

    , & Homeostatic efficiency of tubuloglomerular feedback is reduced in established diabetes mellitus in rats. Am. J. Physiol. 269, F876–F883 (1995).

  152. 152.

    , , , & Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J. Am. Soc. Nephrol. 10, 2569–2576 (1999).

  153. 153.

    et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 5, 610–621 (2017).

  154. 154.

    et al. Bioenergetic characterization of mouse podocytes. Am. J. Physiol. Cell Physiol. 299, C464–C476 (2010).

  155. 155.

    et al. Glycolysis, but not mitochondria, responsible for intracellular ATP distribution in cortical area of podocytes. Sci. Rep. 5, 18575 (2015).

  156. 156.

    , , & Endothelial cell and platelet bioenergetics: effect of glucose and nutrient composition. PLoS ONE 7, e39430 (2012).

  157. 157.

    , & Glucose metabolism in renal tubular function. Kidney Int. 29, 54–67 (1986).

  158. 158.

    & Enzyme distribution along the nephron. Kidney Int. 26, 101–111 (1984).

  159. 159.

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

  160. 160.

    et al. Assessment of early diabetic renal changes with hyperpolarized [1-(13) C]pyruvate. Diabetes Metab. Res. Rev. 29, 125–129 (2013).

  161. 161.

    , , , & Substrate oxidation by defined single nephron segments of rat kidney. Int. J. Biochem. 12, 53–54 (1980).

  162. 162.

    & Cell survival in the hostile environment of the renal medulla. Annu. Rev. Physiol. 67, 531–555 (2005).

  163. 163.

    , & Tissue preferences for fatty acid and glucose oxidation. J. Biol. Chem. 212, 921–933 (1955).

  164. 164.

    & Metabolism of free fatty acids by myocardium and kidney. Am. J. Physiol. 206, 153–158 (1964).

  165. 165.

    & Substrate-utilization of the human kidney. Nature 209, 1244–1245 (1966).

  166. 166.

    , , & Fatty acids in energy metabolism of the central nervous system. Biomed. Res. Int. 2014, 472459 (2014).

  167. 167.

    , , , & Myocardial fatty acid metabolism in health and disease. Physiol. Rev. 90, 207–258 (2010).

  168. 168.

    , , & The biochemistry and physiology of mitochondrial fatty acid beta-oxidation and its genetic disorders. Annu. Rev. Physiol. 78, 23–44 (2016).

  169. 169.

    Diabetic dyslipidemia: basic mechanisms underlying the common hypertriglyceridemia and low HDL cholesterol levels. Diabetes 45 (Suppl. 3), S27–S30 (1996).

  170. 170.

    & Dyslipidemia in chronic kidney disease: managing a high-risk combination. Postgrad. Med. 121, 54–61 (2009).

  171. 171.

    Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences. Am. J. Physiol. Renal Physiol. 290, F262–F272 (2006).

  172. 172.

    , , , & Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J. Lipid Res. 55, 561–572 (2014).

  173. 173.

    et al. Studies of renal injury III: lipid-induced nephropathy in type II diabetes. Kidney Int. 57, 92–104 (2000).

  174. 174.

    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).

  175. 175.

    et al. Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. Diabetes 54, 2328–2335 (2005).

  176. 176.

    & Lovastatin for lowering cholesterol levels in non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 318, 81–86 (1988).

  177. 177.

    et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 65, 1190–1195 (2016). This research shows the effects on fatty acid metabolism that occur following therapy to decrease proximal tubule Na+ and glucose reabsorption.

  178. 178.

    et al. Oxidation of fatty acids is the source of increased mitochondrial reactive oxygen species production in kidney cortical tubules in early diabetes. Diabetes 61, 2074–2083 (2012).

  179. 179.

    , & The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease. Curr. Diab. Rep. 15, 40 (2015).

  180. 180.

    & The unique character of cardiovascular disease in chronic kidney disease and its implications for treatment with lipid-lowering drugs. Clin. J. Am. Soc. Nephrol. 2, 766–785 (2007).

  181. 181.

    et al. The effect of long-term aggressive lipid lowering on ischemic and atherosclerotic burden in patients with chronic kidney disease. Am. J. Kidney Dis. 43, 45–52 (2004).

  182. 182.

    et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37–46 (2015). This paper presents a new line of thinking in which fatty acid oxidation is a protective rather than a pathological change in CKD.

  183. 183.

    , & Lipid biology of the podocyte — new perspectives offer new opportunities. Nat. Rev. Nephrol. 10, 379–388 (2014).

  184. 184.

    , , , & Susceptibility of podocytes to palmitic acid is regulated by fatty acid oxidation and inversely depends on acetyl-CoA carboxylases 1 and 2. Am. J. Physiol. Renal Physiol. 306, F401–F409 (2014).

  185. 185.

    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).

  186. 186.

    et al. Albumin-associated free fatty acids induce macropinocytosis in podocytes. J. Clin. Invest. 125, 2307–2316 (2015).

  187. 187.

    et al. Cyclodextrin protects podocytes in diabetic kidney disease. Diabetes 62, 3817–3827 (2013).

  188. 188.

    et al. The effects of dietary cholesterol on experimental diabetic nephropathy. Diabetes Res. 22, 159–169 (1993).

  189. 189.

    , , , & The microbiology of butyrate formation in the human colon. FEMS Microbiol. Lett. 217, 133–139 (2002).

  190. 190.

    , , & Mitochondrial respiratory capacity and Na+- and K+-dependent adenosine triphosphatase-mediated ion transport in the intact renal cell. J. Biol. Chem. 256, 10319–10328 (1981).

  191. 191.

    , & Renal ketone body metabolism. Distribution of 3-oxoacid CoA-transferase and 3-hydroxybutyrate dehydrogenase along the mouse nephron. Hoppe Seylers Z. Physiol. Chem. 364, 1727–1737 (1983).

  192. 192.

    & Diabetic ketoacidosis. Emerg. Med. Clin. North Am. 23, 609–628 (2005).

  193. 193.

    et al. Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 300, E287–295 (2011).

  194. 194.

    et al. Glomerular filtration rate is increased in man by the infusion of both D,L-3-hydroxybutyric acid and sodium D,L-3-hydroxybutyrate. J. Clin. Endocrinol. Metab. 65, 331–338 (1987).

  195. 195.

    et al. Enantioselective determination of 3-hydroxybutyrate in the tissues of normal and streptozotocin-induced diabetic rats of different ages. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 879, 3331–3336 (2011).

  196. 196.

    , & Altered renal intermediary metabolism and the onset of renal dysfunction in the streptozotocin diabetic rat. Biochem. Soc. Trans. 24, 264S (1996).

  197. 197.

    et al. Uptake of ketone bodies in perfused hindquarter and kidney of starved, thyrotoxic, and diabetic rats. Proc. Soc. Exp. Biol. Med. 203, 55–59 (1993).

  198. 198.

    , & Reversible acetylation of PGC-1: connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene 29, 4617–4624 (2010).

  199. 199.

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

  200. 200.

    et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J. 26, 1913–1923 (2007).

  201. 201.

    et al. PGC1alpha drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature 531, 528–532 (2016). This paper links the maintenance of oxidative phosphorylation via preservation of cellular NAD+ to protection against acute renal injury.

  202. 202.

    , , , & Isolation of diabetes-associated kidney genes using differential display. Biochem. Biophys. Res. Commun. 232, 49–53 (1997).

  203. 203.

    , , & Skeletal muscle PGC-1alpha controls whole-body lactate homeostasis through estrogen-related receptor alpha-dependent activation of LDH B and repression of LDH A. Proc. Natl Acad. Sci. USA 110, 8738–8743 (2013).

  204. 204.

    et al. Rap1 ameliorates renal tubular injury in diabetic nephropathy. Diabetes 63, 1366–1380 (2014).

  205. 205.

    et al. Rap1b GTPase ameliorates glucose-induced mitochondrial dysfunction. J. Am. Soc. Nephrol. 19, 2293–2301 (2008).

  206. 206.

    & Effect of insulin therapy on renal hemodynamic response to amino acids and renal hypertrophy in non-insulin-dependent diabetes. Kidney Int. 42, 167–173 (1992).

  207. 207.

    , , & Effects of amino acids and glucagon on renal hemodynamics in type 1 diabetes. Am. J. Physiol. Renal Physiol. 282, F103–F112 (2002).

  208. 208.

    , , & Role of glutamine in human carbohydrate metabolism in kidney and other tissues. Kidney Int. 55, 778–792 (1999).

  209. 209.

    & Renal oxygen consumption, thermogenesis, and amino acid utilization during i.v. infusion of amino acids in man. Am. J. Physiol. 267, E648–E655 (1994).

  210. 210.

    et al. Human kidney and liver gluconeogenesis: evidence for organ substrate selectivity. Am. J. Physiol. 274, E817–E826 (1998).

  211. 211.

    & Glutamine metabolism: role in acid-base balance. Biochem. Mol. Biol. Educ. 32, 291–304 (2004).

  212. 212.

    On the stimulation of gluconeogenesis by L-lysine in isolated rat kidney cortex tubules. Biochim. Biophys. Acta 392, 255–270 (1975).

  213. 213.

    [No authors listed.] GLS. The Human Protein Atlas (2017).

  214. 214.

    Renal substrate utilization in normal and acidotic rats. Am. J. Physiol. 253, F351–F357 (1987).

  215. 215.

    & Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 16, 461–472 (2015).

  216. 216.

    & Autophagy in diabetic nephropathy. J. Endocrinol. 224, R15–R30 (2015).

  217. 217.

    et al. Systems biology analysis reveals role of MDM2 in diabetic nephropathy. JCI Insight 1, e87877 (2016).

  218. 218.

    & Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012). This paper provides an excellent overarching view of the mitochondria.

  219. 219.

    et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433–446 (2008).

  220. 220.

    Organelle dynamics: fusing for stability. Nat. Rev. Mol. Cell Biol. 11, 391 (2010).

  221. 221.

    , & Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J. Biol. Chem. 280, 26185–26192 (2005).

  222. 222.

    , , , & Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology. Kidney Int. 83, 568–581 (2013).

  223. 223.

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

  224. 224.

    & New insights into molecular mechanisms of diabetic kidney disease. Am. J. Kidney Dis. 63, S63–S83 (2014).

  225. 225.

    et al. Dynamin-related protein 1 deficiency improves mitochondrial fitness and protects against progression of diabetic nephropathy. J. Am. Soc. Nephrol. 27, 2733–2747 (2016). This paper presents studies that demonstrate a causative link between disruption of mitochondrial networking and DKD.

  226. 226.

    , , & Disruption of renal tubular mitochondrial quality control by Myo-inositol oxygenase in diabetic kidney disease. J. Am. Soc. Nephrol. 26, 1304–1321 (2015).

  227. 227.

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

  228. 228.

    & Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep. 8, 939–944 (2007).

  229. 229.

    & Mitochondrial fission in apoptosis. Nat. Rev. Mol. Cell Biol. 6, 657–663 (2005).

  230. 230.

    & Mitochondrial fission, fusion, and stress. Science 337, 1062–1065 (2012).

  231. 231.

    et al. ER tubules mark sites of mitochondrial division. Science 334, 358–362 (2011).

  232. 232.

    & Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat. Rev. Mol. Cell Biol. 13, 607–625 (2012).

  233. 233.

    , , & Calcium in cell injury and death. Annu. Rev. Pathol. 1, 405–434 (2006).

  234. 234.

    et al. Isoform- and species-specific control of inositol 1,4,5-trisphosphate (IP3) receptors by reactive oxygen species. J. Biol. Chem. 289, 8170–8181 (2014).

  235. 235.

    , , , & Uncoupling of ER-mitochondrial calcium communication by transforming growth factor-beta. Am. J. Physiol. Renal Physiol. 295, F1303–F1312 (2008).

  236. 236.

    & The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 20, 31–42 (2013).

  237. 237.

    & Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy? Br. J. Pharmacol. 171, 1917–1942 (2014).

  238. 238.

    et al. Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway. Sci. Rep. 6, 29196 (2016).

  239. 239.

    et al. FoxO1 promotes mitophagy in the podocytes of diabetic male mice via the PINK1/Parkin pathway. Endocrinology 158, 2155–2167 (2017).

  240. 240.

    et al. The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1. Redox Biol. 11, 297–311 (2017).

  241. 241.

    et al. Expression, localization, and function of the thioredoxin system in diabetic nephropathy. J. Am. Soc. Nephrol. 20, 730–741 (2009).

  242. 242.

    et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Invest. 121, 2197–2209 (2011).

  243. 243.

    et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J. Clin. Invest. 121, 2181–2196 (2011).

  244. 244.

    & Sending out an SOS: mitochondria as a signaling hub. Front. Cell Dev. Biol. 4, 109 (2016).

  245. 245.

    , & Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell Biol. 17, 213–226 (2016).

  246. 246.

    & Mitohormesis. Cell Metab. 19, 757–766 (2014).

  247. 247.

    , , , & Interaction of PPARalpha with the canonic wnt pathway in the regulation of renal fibrosis. Diabetes 65, 3730–3743 (2016).

  248. 248.

    et al. Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy. Free Radic. Biol. Med. 93, 94–109 (2016).

  249. 249.

    , , & Impaired mitochondrial respiratory functions and oxidative stress in streptozotocin-induced diabetic rats. Int. J. Mol. Sci. 12, 3133–3147 (2011).

  250. 250.

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

  251. 251.

    , , & AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).

  252. 252.

    & From calcium to NF-kappa B signaling pathways in neurons. Mol. Cell. Biol. 23, 2680–2698 (2003).

  253. 253.

    et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404, 787–790 (2000).

  254. 254.

    Mitochondrial dysfunction in the diabetic kidney. Adv. Exp. Med. Biol. 982, 553–562 (2017).

  255. 255.

    The role of BCL-2 family members in acute kidney injury. Semin. Nephrol. 36, 237–250 (2016).

  256. 256.

    et al. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proc. Natl Acad. Sci. USA 111, E2501–E2509 (2014).

  257. 257.

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

  258. 258.

    et al. Real-time in vivo mitochondrial redox assessment confirms enhanced mitochondrial reactive oxygen species in diabetic nephropathy. Kidney Int. 92, 1282–1287 (2017).

  259. 259.

    et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J. Clin. Invest. 115, 3587–3593 (2005).

  260. 260.

    , , , & Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 350, 664–671 (2004).

  261. 261.

    , , , & Mitochondrial disease and endocrine dysfunction. Nat. Rev. Endocrinol. 13, 92–104 (2017).

  262. 262.

    et al. Genetic risk factors affecting mitochondrial function are associated with kidney disease in people with type 1 diabetes. Diabet. Med. 32, 1104–1109 (2015). This study shows that genes that alter mitochondrial function are altered in individuals with DKD.

  263. 263.

    , & Distinct methylation patterns in genes that affect mitochondrial function are associated with kidney disease in blood-derived DNA from individuals with type 1 diabetes. Diabet. Med. 32, 1110–1115 (2015).

  264. 264.

    et al. Mitochondrial diseases. Nat. Rev. Dis. Primers 2, 16080 (2016).

  265. 265.

    , , , & Pathogenic mitochondrial DNA mutations are common in the general population. Am. J. Hum. Genet. 83, 254–260 (2008). This article presents a challenge to the dogma that mtDNA mutations are not common in the general population.

  266. 266.

    et al. Population prevalence of the MELAS A3243G mutation. Mitochondrion 7, 230–233 (2007).

  267. 267.

    et al. Prevalence of mitochondrial 1555A→G mutation in adults of European descent. N. Engl. J. Med. 360, 642–644 (2009).

  268. 268.

    , & Human mitochondrial DNA: roles of inherited and somatic mutations. Nat. Rev. Genet. 13, 878–890 (2012).

  269. 269.

    et al. Mitochondrial DNA backgrounds might modulate diabetes complications rather than T2DM as a whole. PLoS ONE 6, e21029 (2011).

  270. 270.

    et al. Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: implications for population susceptibility to diseases. Biochim. Biophys. Acta 1842, 208–219 (2014). This paper describes a novel hypothesis in which incompatibility between mtDNA haplotype and nuclear haplotype could affect susceptibility to disease.

  271. 271.

    et al. Mitochondrial DNA variants can mediate methylation status of inflammation, angiogenesis and signaling genes. Hum. Mol. Genet. 24, 4491–4503 (2015).

  272. 272.

    et al. Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains. Acta Neuropathol. Commun. 5, 13 (2017).

  273. 273.

    et al. Spectrum of combined respiratory chain defects. J. Inherit Metab. Dis. 38, 629–640 (2015).

  274. 274.

    , Complications Trial / & Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 290, 2159–2167 (2003).

  275. 275.

    , & Clinical review 2: The “metabolic memory”: is more than just tight glucose control necessary to prevent diabetic complications? J. Clin. Endocrinol. Metab. 94, 410–415 (2009).

  276. 276.

    Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: the DCCT/EDIC study 30-year follow-up. Diabetes Care 39, 686–693 (2016).

  277. 277.

    et al. Ubiquinone (coenzyme Q10) prevents renal mitochondrial dysfunction in an experimental model of type 2 diabetes. Free Radic. Biol. Med. 52, 716–723 (2012).

  278. 278.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  279. 279.

    et al. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol. 71, 543–552 (2014).

  280. 280.

    & Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann. NY Acad. Sci. 1201, 96–103 (2010).

  281. 281.

    et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J. Biol. Chem. 276, 4588–4596 (2001).

  282. 282.

    et al. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease. Mov. Disord. 25, 1670–1674 (2010).

  283. 283.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  284. 284.

    et al. Prevention of diabetic nephropathy in Ins2(+/)(−)(AkitaJ) mice by the mitochondria-targeted therapy MitoQ. Biochem. J. 432, 9–19 (2010).

  285. 285.

    et al. Targeted mitochondrial therapy using MitoQ shows equivalent renoprotection to angiotensin converting enzyme inhibition but no combined synergy in diabetes. Sci. Rep. 7, 15190 (2017).

  286. 286.

    et al. Mitochondria-targeted peptide SS-31 attenuates renal injury via an antioxidant effect in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 310, F547–F559 (2016).

  287. 287.

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

  288. 288.

    et al. A mitochondrial therapeutic reverses visual decline in mouse models of diabetes. Dis. Model. Mech. 8, 701–710 (2015).

  289. 289.

    First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br. J. Pharmacol. 171, 2029–2050 (2014).

  290. 290.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  291. 291.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  292. 292.

    et al. Mitochondrial disorders in children: toward development of small-molecule treatment strategies. EMBO Mol. Med. 8, 311–327 (2016).

  293. 293.

    et al. KH176 under development for rare mitochondrial disease: a first in man randomized controlled clinical trial in healthy male volunteers. Orphanet J. Rare Dis. 12, 163 (2017).

  294. 294.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  295. 295.

    & Fatty acid import into mitochondria. Biochim. Biophys. Acta 1486, 1–17 (2000).

  296. 296.

    et al. Ameliorating hypertension and insulin resistance in subjects at increased cardiovascular risk: effects of acetyl-L-carnitine therapy. Hypertension 54, 567–574 (2009).

  297. 297.

    , , , & Ameliorating effects of L-carnitine on diabetic podocyte injury. J. Med. Food 13, 1324–1330 (2010).

  298. 298.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  299. 299.

    , & Oral acetyl-L-carnitine therapy and insulin resistance. Hypertension 55, e26 (2010).

  300. 300.

    , , , & Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care 28, 89–94 (2005).

  301. 301.

    & Turn up the power — pharmacological activation of mitochondrial biogenesis in mouse models. Br. J. Pharmacol. 171, 1818–1836 (2014).

  302. 302.

    , & Effect of chronic clofibrate administration on mitochondrial fatty acid oxidation. Biochem. Pharmacol. 25, 1285–1292 (1976).

  303. 303.

    , , & Mitochondrial and peroxisomal fatty acid oxidation in liver homogenates and isolated hepatocytes from control and clofibrate-treated rats. J. Biol. Chem. 254, 4585–4595 (1979).

  304. 304.

    & Paradoxical effects of clofibrate on liver and muscle metabolism in rats. Induction of myotonia and alteration of fatty acid and glucose oxidation. J. Clin. Invest. 64, 405–412 (1979).

  305. 305.

    et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 54, 280–290 (2011).

  306. 306.

    , & The combined strategy with PPARalpha agonism and AT(1) receptor antagonism is not superior relative to their individual treatment approach in preventing the induction of nephropathy in the diabetic rat. Pharmacol. Res. 66, 349–356 (2012).

  307. 307.

    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).

  308. 308.

    , & Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons. Cardiovasc. Diabetol. 4, 14 (2005).

  309. 309.

    et al. Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptor-coactivator (PGC)-1alpha gene transcription: an autoregulatory loop controls PGC-1alpha expression in adipocytes via peroxisome proliferator-activated receptor-gamma coactivation. Endocrinology 147, 2829–2838 (2006).

  310. 310.

    et al. PPARdelta, but not PPARalpha, activates PGC-1alpha gene transcription in muscle. Biochem. Biophys. Res. Commun. 354, 1021–1027 (2007).

  311. 311.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  312. 312.

    et al. Bezafibrate and medroxyprogesterone acetate in resistant and relapsed endemic Burkitt lymphoma in Malawi; an open-label, single-arm, phase 2 study (ISRCTN34303497). Br. J. Haematol. 164, 888–890 (2014).

  313. 313.

    & Idebenone and neuroprotection: antioxidant, pro-oxidant, or electron carrier? J. Bioenerg. Biomembr. 47, 111–118 (2015).

  314. 314.

    et al. Persistence of the treatment effect of idebenone in Leber's hereditary optic neuropathy. Brain 136, e230 (2013).

  315. 315.

    et al. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain 134, 2677–2686 (2011).

  316. 316.

    et al. Idebenone in Friedreich ataxia cardiomyopathy-results from a 6-month phase III study (IONIA). Am. Heart J. 161, 639–645.e1 (2011).

  317. 317.

    et al. Glutathione: a redox signature in monitoring EPI-743 therapy in children with mitochondrial encephalomyopathies. Mol. Genet. Metab. 109, 208–214 (2013).

  318. 318.

    et al. EPI-743 reverses the progression of the pediatric mitochondrial disease — genetically defined Leigh Syndrome. Mol. Genet. Metab. 107, 383–388 (2012).

  319. 319.

    et al. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch. Neurol. 69, 331–338 (2012).

  320. 320.

    et al. A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease. Mov. Disord. 32, 932–936 (2017).

  321. 321.

    et al. A randomized controlled crossover trial with delayed-release cysteamine bitartrate in nephropathic cystinosis: effectiveness on white blood cell cystine levels and comparison of safety. Clin. J. Am. Soc. Nephrol. 7, 1112–1120 (2012).

  322. 322.

    & Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. Biochem. J. 268, 153–160 (1990).

  323. 323.

    et al. Involvement of cyclophilin D in the activation of a mitochondrial pore by Ca2+ and oxidant stress. Eur. J. Biochem. 238, 166–172 (1996).

  324. 324.

    et al. Inhibition of human immunodeficiency virus type 1 replication in human cells by Debio-025, a novel cyclophilin binding agent. Antimicrob. Agents Chemother. 52, 1302–1317 (2008).

  325. 325.

    et al. The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects in Col6a1−/− myopathic mice. Br. J. Pharmacol. 157, 1045–1052 (2009).

  326. 326.

    et al. Alisporivir plus ribavirin, interferon free or in combination with pegylated interferon, for hepatitis C virus genotype 2 or 3 infection. Hepatology 62, 1013–1023 (2015).

  327. 327.

    et al. The cyclophilin inhibitor alisporivir prevents hepatitis C virus-mediated mitochondrial dysfunction. Hepatology 55, 1333–1343 (2012).

  328. 328.

    et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: a randomized phase III study (ALLY-3+). Hepatology 63, 1430–1441 (2016).

  329. 329.

    et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 61, 1127–1135 (2015).

  330. 330.

    et al. Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naive patients with chronic HCV genotype 1 infection (ESSENTIAL II). Aliment. Pharmacol. Ther. 42, 829–844 (2015).

  331. 331.

    US National Library of Medicine. ClinicalTrials.gov (2016).

  332. 332.

    et al. Curcumin ameliorates diabetic nephropathy by suppressing NLRP3 inflammasome signaling. Biomed. Res. Int. 2017, 1516985 (2017).

  333. 333.

    & Effects of curcumin and captopril on the functions of kidney and nerve in streptozotocin-induced diabetic rats: role of angiotensin converting enzyme 1. Appl. Physiol. Nutr. Metab. 40, 1061–1067 (2015).

  334. 334.

    et al. Curcumin attenuates urinary excretion of albumin in type II diabetic patients with enhancing nuclear factor erythroid-derived 2-like 2 (Nrf2) system and repressing inflammatory signaling efficacies. Exp. Clin. Endocrinol. Diabetes 123, 360–367 (2015).

  335. 335.

    et al. The effect of dietary supplementation with curcumin on redox status and Nrf2 activation in patients with nondiabetic or diabetic proteinuric chronic kidney disease: a pilot study. J. Ren. Nutr. 26, 237–244 (2016).

  336. 336.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  337. 337.

    et al. In a type 2 diabetic nephropathy rat model, the improvement of obesity by a low calorie diet reduces oxidative/carbonyl stress and prevents diabetic nephropathy. Nephrol. Dial Transplant. 20, 2661–2669 (2005).

  338. 338.

    , , , & Intermittent fasting prevents the progression of type I diabetic nephropathy in rats and changes the expression of Sir2 and p53. FEBS Lett. 581, 1071–1078 (2007).

  339. 339.

    et al. Calorie restriction improves cardiovascular risk factors via reduction of mitochondrial reactive oxygen species in type II diabetic rats. J. Pharmacol. Exp. Ther. 320, 535–543 (2007).

  340. 340.

    et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).

  341. 341.

    et al. Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases myocardial triglyceride content and improves myocardial function. J. Am. Coll. Cardiol. 52, 1006–1012 (2008).

  342. 342.

    et al. Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. Am. J. Physiol. Renal Physiol. 296, F700–F708 (2009).

  343. 343.

    & Exercise training for adults with chronic kidney disease. Cochrane Database Syst. Rev. 10, CD003236 (2011).

  344. 344.

    et al. Structured exercise in obese diabetic patients with chronic kidney disease: a randomized controlled trial. Am. J. Nephrol. 44, 54–62 (2016).

  345. 345.

    et al. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. J. Biol. Chem. 282, 194–199 (2007).

  346. 346.

    et al. Effects of resveratrol supplementation in Nrf2 and NF-kappaB expressions in nondialyzed chronic kidney disease patients: a randomized, double-blind, placebo-controlled, crossover clinical trial. J. Ren. Nutr. 26, 401–406 (2016).

  347. 347.

    et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006).

  348. 348.

    et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127, 1109–1122 (2006).

  349. 349.

    et al. Effects of resveratrol and SIRT1 on PGC-1alpha activity and mitochondrial biogenesis: a reevaluation. PLoS Biol. 11, e1001603 (2013).

  350. 350.

    et al. Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation following endurance exercise. J. Biol. Chem. 286, 30561–30570 (2011).

  351. 351.

    et al. Resveratrol supplementation in patients with non-alcoholic fatty liver disease: systematic review and meta-analysis. J. Gastrointestin. Liver Dis. 26, 59–67 (2017).

  352. 352.

    et al. No beneficial effects of resveratrol on the metabolic syndrome: a randomized placebo-controlled clinical trial. J. Clin. Endocrinol. Metab. 102, 1642–1651 (2017).

  353. 353.

    et al. Effect of resveratrol on walking performance in older people with peripheral artery disease: the RESTORE randomized clinical trial. JAMA Cardiol. 2, 902–907 (2017).

  354. 354.

    et al. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE 12, e0186459 (2017).

  355. 355.

    et al. Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD(+) levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. NPJ Aging Mech. Dis. 3, 17 (2017).

  356. 356.

    , , & The mitochondrial respiratory chain is partially organized in a supercomplex assembly: kinetic evidence using flux control analysis. J. Biol. Chem. 279, 36562–36569 (2004).

  357. 357.

    & The quaternary structure of the Saccharomyces cerevisiae succinate dehydrogenase. Homology modeling, cofactor docking, and molecular dynamics simulation studies. J. Biol. Chem. 279, 9424–9431 (2004).

  358. 358.

    et al. Electron transfer by domain movement in cytochrome bc1. Nature 392, 677–684 (1998).

  359. 359.

    , & Catalytic site cooperativity of beef heart mitochondrial F1 adenosine triphosphatase. Correlations of initial velocity, bound intermediate, and oxygen exchange measurements with an alternating three-site model. J. Biol. Chem. 257, 12030–12038 (1982).

  360. 360.

    , & Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol. Rev. 90, 367–417 (2010).

  361. 361.

    Metabolism of fatty acids. Annu. Rev. Biochem. 38, 159–212 (1969).

  362. 362.

    et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125 (2010).

  363. 363.

    et al. De novo mtDNA point mutations are common and have a low recurrence risk. J. Med. Genet. 54, 73–83 (2017).

  364. 364.

    et al. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nat. Genet. 26, 176–181 (2000).

  365. 365.

    Renal manifestations of genetic mitochondrial disease. Int. J. Nephrol. Renovasc. Dis. 7, 57–67 (2014).

  366. 366.

    et al. Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. PLoS Genet. 13, e1006620 (2017).

  367. 367.

    et al. The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease. J. Med. Genet. (2016).

  368. 368.

    et al. Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. Hum. Mol. Genet. 24, 2297–2307 (2015).

  369. 369.

    et al. TRMT5 mutations cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am. J. Hum. Genet. 97, 319–328 (2015).

  370. 370.

    et al. Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy. Am. J. Hum. Genet. 93, 482–495 (2013).

  371. 371.

    et al. Biallelic mutations in TMEM126B cause severe complex I deficiency with a variable clinical phenotype. Am. J. Hum. Genet. 99, 217–227 (2016).

  372. 372.

    et al. Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6. Hum. Mol. Genet. 25, 4062–4079 (2016).

  373. 373.

    et al. 1H NMR-based metabonomic analysis of serum and urine in a nonhuman primate model of diabetic nephropathy. Mol. Biosyst 9, 2645–2652 (2013).

  374. 374.

    et al. The Munich MIDY Pig Biobank — a unique resource for studying organ crosstalk in diabetes. Mol. Metab. 6, 931–940 (2017).

  375. 375.

    et al. Plasma esterified and non-esterified fatty acids metabolic profiling using gas chromatography-mass spectrometry and its application in the study of diabetic mellitus and diabetic nephropathy. Anal. Chim. Acta 689, 85–91 (2011).

  376. 376.

    , , , & Changes in metabolism of rat kidney and liver caused by experimental diabetes and by dietary sucrose. Diabetologia 22, 285–288 (1982).

  377. 377.

    et al. Dietary polyunsaturated fatty acids slow the progression of diabetic nephropathy in streptozotocin-induced diabetic rats. Nutr. Res. 30, 217–225 (2010).

  378. 378.

    et al. Elevated urinary D-lactate levels in patients with diabetes and microalbuminuria. J. Pharm. Biomed. Anal. 116, 65–70 (2015).

  379. 379.

    et al. Determination of serum D-lactic and L-lactic acids in normal subjects and diabetic patients by column-switching HPLC with pre-column fluorescence derivatization. Anal. Bioanal. Chem. 377, 886–891 (2003).

  380. 380.

    et al. L(+) and D(−) lactate are increased in plasma and urine samples of type 2 diabetes as measured by a simultaneous quantification of L(+) and D(−) lactate by reversed-phase liquid chromatography tandem mass spectrometry. Exp. Diabetes Res. 2012, 234812 (2012).

  381. 381.

    et al. Determination of time-dependent accumulation of D-lactate in the streptozotocin-induced diabetic rat kidney by column-switching HPLC with fluorescence detection. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 879, 3214–3219 (2011).

  382. 382.

    et al. A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. Physiol. Genom. 29, 99–108 (2007).

  383. 383.

    , , , & Interorgan metabolism of amino acids in streptozotocin-diabetic ketoacidotic rat. Am. J. Physiol. 244, E151–E158 (1983).

  384. 384.

    , & Increased poly-(R)-3-hydroxybutyrate concentrations in streptozotocin (STZ) diabetic rats. Acta Diabetol 40, 91–94 (2003).

  385. 385.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  386. 386.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  387. 387.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  388. 388.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  389. 389.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  390. 390.

    US National Library of Medicine. ClinicalTrials.gov (2017).

Download references

Acknowledgements

J.M.F. was supported by fellowships from the National Health and Medical Research Council of Australia (NH&MRC; 10045031 and 102935) and grants from the US National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Diabetes Complications Consortium (25034–61), the NH&MRC (1023664), Kidney Health Australia and the Mater Foundation. D.R.T. was supported by a Principal Research Fellowship and grants from the NH&MRC (1022896, 1068409 and 1107094).

Author information

Affiliations

  1. Glycation and Diabetes Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.

    • Josephine M. Forbes
  2. Mater Clinical School, School of Medicine, The University of Queensland, St Lucia, Queensland, Australia.

    • Josephine M. Forbes
  3. Departments of Medicine and Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.

    • Josephine M. Forbes
    •  & David R. Thorburn
  4. Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.

    • David R. Thorburn

Authors

  1. Search for Josephine M. Forbes in:

  2. Search for David R. Thorburn in:

Contributions

Both authors researched the data, wrote the article and reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Josephine M. Forbes.

Supplementary information

Word documents

  1. 1.

    Supplementary information S1 (table)

    Oxygen delivery and consumption at rest and mitochondrial density by organ.

Glossary

Arterio-venous shunting

Mixing of oxygenated and deoxygenated blood through channels between the arterial and venous systems that bypass capillary networks.

Intraglomerular capillary sphincters

Narrowings in glomerular capillaries that are encircled with smooth muscle. Dilatation or constriction of these sphincters modulates blood flow.

Tubuloglomerular feedback

An adaptive mechanism that links the rate of glomerular filtration to the concentration of salt in the tubule fluid, which is sensed by specialized cells in the macula densa.

Fanconi syndrome

A rare syndrome in which the proximal tubules of the kidney are unable to reabsorb solutes adequately. Fanconi syndrome may be inherited or caused by severe renal stressors.

Leigh disease

A rare inherited (via either nuclear or mtDNA) neurometabolic syndrome that causes death in the first few years of life and may have renal manifestations.

State III respiration

A high steady state of mitochondrial respiration (OXPHOS) that occurs following the addition of adenosine diphosphate in the presence of OXPHOS substrates.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrneph.2018.9