Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Renal involvement in the mitochondrial cytopathies

Patrick Niaudet, MD
Section Editors
Tej K Mattoo, MD, DCH, FRCP
Marc C Patterson, MD, FRACP
Deputy Editor
Melanie S Kim, MD


Mitochondrial cytopathies are a heterogeneous group of disorders characterized by genetic defects in one or more of the enzymatic complexes of the respiratory chain. These disorders impair oxidative phosphorylation [1-3], and were long regarded as neuromuscular diseases. However, they also cause dysfunction of the kidney and other organs because many tissues, in addition to muscle and brain, are highly dependent upon mitochondrial energy supply [4-7]. (See "Mitochondrial myopathies: Clinical features and diagnosis".)

An overview of the mitochondrial cytopathies, with an emphasis on associated kidney disorders, is presented here. A brief review of the physiology and genetics of the mitochondria is required to fully understand the various clinical manifestations of the mitochondrial cytopathies.


The main function of the mitochondrion is the production of adenosine triphosphate (ATP) through oxidative phosphorylation. Oxidative phosphorylation occurs in the mitochondrial inner membrane, and includes the oxidation of fuel molecules with energy transduction into ATP. During this process, reducing equivalents are transferred to oxygen via the complexes of the mitochondrial respiratory chain. The mitochondrial structure, function, and genetics are discussed separately. (See "Mitochondrial structure, function, and genetics".)


Mutations in both mitochondrial and nuclear genes have been identified in patients with mitochondrial disorder and renal involvement. However, the molecular definition of the genetic mutation underlying mitochondrial respiratory chain defects is complicated by the dual genetic control of respiratory chain proteins, and by the high number of genes involved in the biogenesis and the assembly of the respiratory chain (table 1). All modes of inheritance can be observed in mitochondrial disorders, including mitochondrial DNA (mtDNA) or nuclear gene mutations in sporadic cases; maternal transmission of mtDNA mutations; and autosomal recessive, autosomal dominant, and X-linked inheritance of nuclear gene mutations.

The genetics that underlie a mitochondrial disorder with renal involvement have been identified in only a few patients and families. These will be reviewed in the following sections. Disorders with primarily extrarenal manifestations due to mutations in mitochondrial genes are discussed separately. (See "Mitochondrial myopathies: Clinical features and diagnosis".)


Subscribers log in here

Literature review current through: Apr 2017. | This topic last updated: Sep 01, 2016.
  1. Luft R. The development of mitochondrial medicine. Proc Natl Acad Sci U S A 1994; 91:8731.
  2. Johns DR. Seminars in medicine of the Beth Israel Hospital, Boston. Mitochondrial DNA and disease. N Engl J Med 1995; 333:638.
  3. Niaudet P, Rotig A. The kidney in mitochondrial cytopathies. Kidney Int 1997; 51:1000.
  4. DiMauro S, Bonilla E, Lombes A, et al. Mitochondrial encephalomyopathies. Neurol Clin 1990; 8:483.
  5. Wang J, Wilhelmsson H, Graff C, et al. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nat Genet 1999; 21:133.
  6. Rötig A, Munnich A. Genetic features of mitochondrial respiratory chain disorders. J Am Soc Nephrol 2003; 14:2995.
  7. Martín-Hernández E, García-Silva MT, Vara J, et al. Renal pathology in children with mitochondrial diseases. Pediatr Nephrol 2005; 20:1299.
  8. Guillausseau PJ, Massin P, Dubois-LaForgue D, et al. Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med 2001; 134:721.
  9. Iwasaki N, Babazono T, Tsuchiya K, et al. Prevalence of A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene in Japanese patients with diabetes mellitus and end stage renal disease. J Hum Genet 2001; 46:330.
  10. Majander A, Suomalainen A, Vettenranta K, et al. Congenital hypoplastic anemia, diabetes, and severe renal tubular dysfunction associated with a mitochondrial DNA deletion. Pediatr Res 1991; 30:327.
  11. Rötig A, Goutières F, Niaudet P, et al. Deletion of mitochondrial DNA in patient with chronic tubulointerstitial nephritis. J Pediatr 1995; 126:597.
  12. D'Aco KE, Manno M, Clarke C, et al. Mitochondrial tRNA(Phe) mutation as a cause of end-stage renal disease in childhood. Pediatr Nephrol 2013; 28:515.
  13. Carrozzo R, Bornstein B, Lucioli S, et al. Mutation analysis in 16 patients with mtDNA depletion. Hum Mutat 2003; 21:453.
  14. Moraes CT, Shanske S, Tritschler HJ, et al. mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am J Hum Genet 1991; 48:492.
  15. Quinzii C, Naini A, Salviati L, et al. A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J Hum Genet 2006; 78:345.
  16. Heeringa SF, Chernin G, Chaki M, et al. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 2011; 121:2013.
  17. López LC, Schuelke M, Quinzii CM, et al. Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum Genet 2006; 79:1125.
  18. Ashraf S, Gee HY, Woerner S, et al. ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest 2013; 123:5179.
  19. Vasta V, Merritt JL 2nd, Saneto RP, Hahn SH. Next-generation sequencing for mitochondrial diseases: a wide diagnostic spectrum. Pediatr Int 2012; 54:585.
  20. Valnot I, von Kleist-Retzow JC, Barrientos A, et al. A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency. Hum Mol Genet 2000; 9:1245.
  21. de Lonlay P, Valnot I, Barrientos A, et al. A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nat Genet 2001; 29:57.
  22. Magner M, Dvorakova V, Tesarova M, et al. TMEM70 deficiency: long-term outcome of 48 patients. J Inherit Metab Dis 2015; 38:417.
  23. Tay SK, Sacconi S, Akman HO, et al. Unusual clinical presentations in four cases of Leigh disease, cytochrome C oxidase deficiency, and SURF1 gene mutations. J Child Neurol 2005; 20:670.
  24. Tucker EJ, Wanschers BF, Szklarczyk R, et al. Mutations in the UQCC1-interacting protein, UQCC2, cause human complex III deficiency associated with perturbed cytochrome b protein expression. PLoS Genet 2013; 9:e1004034.
  25. Neiberger RE, George JC, Perkins LA, et al. Renal manifestations of congenital lactic acidosis. Am J Kidney Dis 2002; 39:12.
  26. Dinour D, Mini S, Polak-Charcon S, et al. Progressive nephropathy associated with mitochondrial tRNA gene mutation. Clin Nephrol 2004; 62:149.
  27. Emma F, Bertini E, Salviati L, Montini G. Renal involvement in mitochondrial cytopathies. Pediatr Nephrol 2012; 27:539.
  28. O'Toole JF. Renal manifestations of genetic mitochondrial disease. Int J Nephrol Renovasc Dis 2014; 7:57.
  29. Egger J, Lake BD, Wilson J. Mitochondrial cytopathy. A multisystem disorder with ragged red fibres on muscle biopsy. Arch Dis Child 1981; 56:741.
  30. Rötig A, Bessis JL, Romero N, et al. Maternally inherited duplication of the mitochondrial genome in a syndrome of proximal tubulopathy, diabetes mellitus, and cerebellar ataxia. Am J Hum Genet 1992; 50:364.
  31. DiMauro S, Mendell JR, Sahenk Z, et al. Fatal infantile mitochondrial myopathy and renal dysfunction due to cytochrome-c-oxidase deficiency. Neurology 1980; 30:795.
  32. Hurvitz H, Elpeleg ON, Barash V, et al. Glycogen storage disease, Fanconi nephropathy, abnormal galactose metabolism and mitochondrial myopathy. Eur J Pediatr 1989; 149:48.
  33. Kitano A, Nishiyama S, Miike T, et al. Mitochondrial cytopathy with lactic acidosis, carnitine deficiency and DeToni-Fanconi-Debré syndrome. Brain Dev 1986; 8:289.
  34. Morris AA, Taylor RW, Birch-Machin MA, et al. Neonatal Fanconi syndrome due to deficiency of complex III of the respiratory chain. Pediatr Nephrol 1995; 9:407.
  35. Niaudet P, Heidet L, Munnich A, et al. Deletion of the mitochondrial DNA in a case of de Toni-Debré-Fanconi syndrome and Pearson syndrome. Pediatr Nephrol 1994; 8:164.
  36. Ogier H, Lombes A, Scholte HR, et al. de Toni-Fanconi-Debré syndrome with Leigh syndrome revealing severe muscle cytochrome c oxidase deficiency. J Pediatr 1988; 112:734.
  37. Szabolcs MJ, Seigle R, Shanske S, et al. Mitochondrial DNA deletion: a cause of chronic tubulointerstitial nephropathy. Kidney Int 1994; 45:1388.
  38. Van Biervliet JP, Bruinvis L, Ketting D, et al. Hereditary mitochondrial myopathy with lactic acidemia, a De Toni-Fanconi-Debré syndrome, and a defective respiratory chain in voluntary striated muscles. Pediatr Res 1977; 11:1088.
  39. Eviatar L, Shanske S, Gauthier B, et al. Kearns-Sayre syndrome presenting as renal tubular acidosis. Neurology 1990; 40:1761.
  40. Gruskin AB, Patel MS, Linshaw M, et al. Renal function studies and kidney pyruvate carboxylase in subacute necrotizing encephalomyelopathy (Leigh's syndrome). Pediatr Res 1973; 7:832.
  41. Matsutani H, Mizusawa Y, Shimoda M, et al. Partial deficiency of cytochrome c oxidase with isolated proximal renal tubular acidosis and hypercalciuria. Child Nephrol Urol 1992; 12:221.
  42. Katsanos KH, Elisaf M, Bairaktari E, Tsianos EV. Severe hypomagnesemia and hypoparathyroidism in Kearns-Sayre syndrome. Am J Nephrol 2001; 21:150.
  43. Emma F, Pizzini C, Tessa A, et al. "Bartter-like" phenotype in Kearns-Sayre syndrome. Pediatr Nephrol 2006; 21:355.
  44. Goto Y, Itami N, Kajii N, et al. Renal tubular involvement mimicking Bartter syndrome in a patient with Kearns-Sayre syndrome. J Pediatr 1990; 116:904.
  45. Menegon LF, Amaral TN, Gontijo JA. Renal sodium handling study in an atypical case of Bartter's syndrome associated with mitochondriopathy and sensorineural blindness. Ren Fail 2004; 26:195.
  46. Brun P, Ogier de Baulny H, Peuchmaur, et al. Les atteintes rénales des cytopathies mitochondriales. In: Journées Parisiennes de Pédiatrie, Flammarion Médecine Sciences, Paris 1994. p.227.
  47. Rötig A, Lehnert A, Rustin P, et al. Kidney involvement in mitochondrial disorders. Adv Nephrol Necker Hosp 1995; 24:367.
  48. Doleris LM, Hill GS, Chedin P, et al. Focal segmental glomerulosclerosis associated with mitochondrial cytopathy. Kidney Int 2000; 58:1851.
  49. Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, et al. COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol 2007; 18:2773.
  50. Emma F, Montini G, Parikh SM, Salviati L. Mitochondrial dysfunction in inherited renal disease and acute kidney injury. Nat Rev Nephrol 2016; 12:267.
  51. Desbats MA, Lunardi G, Doimo M, et al. Genetic bases and clinical manifestations of coenzyme Q10 (CoQ 10) deficiency. J Inherit Metab Dis 2015; 38:145.
  52. Rötig A, Appelkvist EL, Geromel V, et al. Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency. Lancet 2000; 356:391.
  53. Barisoni L, Diomedi-Camassei F, Santorelli FM, et al. Collapsing glomerulopathy associated with inherited mitochondrial injury. Kidney Int 2008; 74:237.
  54. Montini G, Malaventura C, Salviati L. Early coenzyme Q10 supplementation in primary coenzyme Q10 deficiency. N Engl J Med 2008; 358:2849.
  55. Dinwiddie DL, Smith LD, Miller NA, et al. Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome. Genomics 2013; 102:148.
  56. Salviati L, Sacconi S, Murer L, et al. Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: a CoQ10-responsive condition. Neurology 2005; 65:606.
  57. Scalais E, Chafai R, Van Coster R, et al. Early myoclonic epilepsy, hypertrophic cardiomyopathy and subsequently a nephrotic syndrome in a patient with CoQ10 deficiency caused by mutations in para-hydroxybenzoate-polyprenyl transferase (COQ2). Eur J Paediatr Neurol 2013; 17:625.
  58. McCarthy HJ, Bierzynska A, Wherlock M, et al. Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2013; 8:637.
  59. Peng M, Falk MJ, Haase VH, et al. Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease. PLoS Genet 2008; 4:e1000061.
  60. Saiki R, Lunceford AL, Shi Y, et al. Coenzyme Q10 supplementation rescues renal disease in Pdss2kd/kd mice with mutations in prenyl diphosphate synthase subunit 2. Am J Physiol Renal Physiol 2008; 295:F1535.
  61. Korkmaz E, Lipska-Ziętkiewicz BS, Boyer O, et al. ADCK4-Associated Glomerulopathy Causes Adolescence-Onset FSGS. J Am Soc Nephrol 2016; 27:63.
  62. Donaldson MD, Warner AA, Trompeter RS, et al. Familial juvenile nephronophthisis, Jeune's syndrome, and associated disorders. Arch Dis Child 1985; 60:426.
  63. Guéry B, Choukroun G, Noël LH, et al. The spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNA(Leu) gene mutation. J Am Soc Nephrol 2003; 14:2099.
  64. Hotta O, Inoue CN, Miyabayashi S, et al. Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation. Kidney Int 2001; 59:1236.
  65. Jansen JJ, Maassen JA, van der Woude FJ, et al. Mutation in mitochondrial tRNA(Leu(UUR)) gene associated with progressive kidney disease. J Am Soc Nephrol 1997; 8:1118.
  66. Kurogouchi F, Oguchi T, Mawatari E, et al. A case of mitochondrial cytopathy with a typical point mutation for MELAS, presenting with severe focal-segmental glomerulosclerosis as main clinical manifestation. Am J Nephrol 1998; 18:551.
  67. Nakamura S, Yoshinari M, Doi Y, et al. Renal complications in patients with diabetes mellitus associated with an A to G mutation of mitochondrial DNA at the 3243 position of leucine tRNA. Diabetes Res Clin Pract 1999; 44:183.
  68. Di Donato S. Multisystem manifestations of mitochondrial disorders. J Neurol 2009; 256:693.
  69. Seidowsky A, Hoffmann M, Glowacki F, et al. Renal involvement in MELAS syndrome - a series of 5 cases and review of the literature. Clin Nephrol 2013; 80:456.
  70. Hirano M, Konishi K, Arata N, et al. Renal complications in a patient with A-to-G mutation of mitochondrial DNA at the 3243 position of leucine tRNA. Intern Med 2002; 41:113.
  71. Hammans SR, Morgan-Hughes JA. Mitochondrial myopathies: Clinical features, investigation, treatment and genetic counseling. In: Mitochondrial Disorders in Neurology, Schapira AHV, DiMauro S (Eds), Butterworth Heinemann, Oxford 1994. p.49.
  72. Parikh S, Karaa A, Goldstein A, et al. Solid organ transplantation in primary mitochondrial disease: Proceed with caution. Mol Genet Metab 2016; 118:178.