Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mitochondrial disease and endocrine dysfunction

Key Points

  • Respiratory chain function and oxidative phosphorylation are affected in primary mitochondrial diseases, and defects in mitochondrial energy metabolism can lead to multisystem organ dysfunction

  • All steroid hormones are synthesized within mitochondria; therefore, lack of ATP generated from mitochondrial dysfunction can lead to impaired hormone production

  • Endocrine abnormalities are well-recognized complications in mitochondrial disorders, observed most frequently in syndromes associated with large-scale mitochondrial DNA rearrangements such as Kearns–Sayre syndrome

  • Hormonal insufficiency from endocrine organ failure can occur, including diabetes mellitus, ovarian failure, adrenal insufficiency and hypoparathyroidism

  • Endocrine dysfunction can be the presenting feature of mitochondrial disease and can precede neurological symptomatology

  • Mitochondrial disease should be suspected in a patient presenting with multisystemic disease and endocrine abnormalities

Abstract

Mitochondria are critical organelles for endocrine health; steroid hormone biosynthesis occurs in these organelles and they provide energy in the form of ATP for hormone production and trafficking. Mitochondrial diseases are multisystem disorders that feature defective oxidative phosphorylation, and are characterized by enormous clinical, biochemical and genetic heterogeneity. To date, mitochondrial diseases have been found to result from >250 monogenic defects encoded across two genomes: the nuclear genome and the ancient circular mitochondrial genome located within mitochondria themselves. Endocrine dysfunction is often observed in genetic mitochondrial diseases and reflects decreased intracellular production or extracellular secretion of hormones. Diabetes mellitus is the most frequently described endocrine disturbance in patients with inherited mitochondrial diseases, but other endocrine manifestations in these patients can include growth hormone deficiency, hypogonadism, adrenal dysfunction, hypoparathyroidism and thyroid disease. Although mitochondrial endocrine dysfunction frequently occurs in the context of multisystem disease, some mitochondrial disorders are characterized by isolated endocrine involvement. Furthermore, additional monogenic mitochondrial endocrine diseases are anticipated to be revealed by the application of genome-wide next-generation sequencing approaches in the future. Understanding the mitochondrial basis of endocrine disturbance is key to developing innovative therapies for patients with mitochondrial diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Oxidative phosphorylation.
Figure 2: Endocrine dysfunction in mitochondrial disease and their associated gene defects.
Figure 3: The diagnosis of endocrine manifestations of mitochondrial disease.

Similar content being viewed by others

References

  1. Chinnery, P. F. Mitochondrial disorders overview in GeneReviews (eds Pagon, R. A. et al.) (University of Washington, Seattle, 1993–2016).

  2. Thorburn, D. R. Mitochondrial disorders: prevalence, myths and advances. J. Inherit. Metab. Dis. 27, 349–362 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Pagano, G. et al. Oxidative stress and mitochondrial dysfunction across broad-ranging pathologies: toward mitochondria-targeted clinical strategies. Oxid. Med. Cell. Longev. 2014, 541230 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Stark, R. & Roden, M. ESCI Award 2006. Mitochondrial function and endocrine diseases. Eur. J. Clin. Invest. 37, 236–248 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Miller, W. L. Steroid hormone synthesis in mitochondria. Mol. Cell. Endocrinol. 379, 62–73 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Calvo, S. E., Clauser, K. R. & Mootha, V. K. MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 44, D1251–D1257 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Kohda, M. et al. A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet. 12, e1005679 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Payne, B. A. et al. Universal heteroplasmy of human mitochondrial DNA. Hum. Mol. Genet. 22, 384–390 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Schaefer, A. M., Walker, M., Turnbull, D. M. & Taylor, R. W. Endocrine disorders in mitochondrial disease. Mol. Cell. Endocrinol. 379, 2–11 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Wang, Z. 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  PubMed  PubMed Central  CAS  Google Scholar 

  11. Shiraiwa, N. et al. Content of mutant mitochondrial DNA and organ dysfunction in a patient with a MELAS subgroup of mitochondrial encephalomyopathies. J. Neurol. Sci. 120, 174–179 (1993).

    Article  CAS  PubMed  Google Scholar 

  12. Sacconi, S. et al. A functionally dominant mitochondrial DNA mutation. Hum. Mol. Genet. 17, 1814–1820 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Munnich, A. et al. Clinical presentation of mitochondrial disorders in childhood. J. Inherit. Metab. Dis. 19, 521–527 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Broomfield, A. et al. Paediatric single mitochondrial DNA deletion disorders: an overlapping spectrum of disease. J. Inherit. Metab. Dis. 38, 445–457 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Quade, A., Zierz, S. & Klingmuller, D. Endocrine abnormalities in mitochondrial myopathy with external ophthalmoplegia. Clin. Investig. 70, 396–402 (1992).

    CAS  PubMed  Google Scholar 

  16. DiMauro, S. & Hirano, M. Mitochondrial DNA Deletion Syndromes in GeneReviews (eds Pagon, R. A. et al.) (University of Washington, Seattle, 1993–2016).

  17. Sanaker, P. S., Husebye, E. S., Fondenes, O. & Bindoff, L. A. Clinical evolution of Kearns-Sayre syndrome with polyendocrinopathy and respiratory failure. Acta Neurol. Scand. Suppl. 187, 64–67 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Maechler, P. Mitochondrial function and insulin secretion. Mol. Cell. Endocrinol. 379, 12–18 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Maassen, J. A. et al. Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes 53 (Suppl. 1), S103–S109 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Nesbitt, V. et al. The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation—implications for diagnosis and management. J. Neurol. Neurosurg. Psychiatry 84, 936–938 (2013).

    Article  PubMed  Google Scholar 

  21. Ohkubo, K. et al. Mitochondrial gene mutations in the tRNA(Leu(UUR)) region and diabetes: prevalence and clinical phenotypes in Japan. Clin. Chem. 47, 1641–1648 (2001).

    CAS  PubMed  Google Scholar 

  22. Murphy, R., Turnbull, D. M., Walker, M. & Hattersley, A. T. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet. Med. 25, 383–399 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Kishimoto, M. et al. Diabetes mellitus carrying a mutation in the mitochondrial tRNA(Leu(UUR)) gene. Diabetologia 38, 193–200 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Karaa, A. & Goldstein, A. The spectrum of clinical presentation, diagnosis, and management of mitochondrial forms of diabetes. Pediatr. Diabetes 16, 1–9 (2015).

    Article  PubMed  Google Scholar 

  25. Whittaker, R. G. et al. Prevalence and progression of diabetes in mitochondrial disease. Diabetologia 50, 2085–2089 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Mancuso, M. et al. Phenotypic heterogeneity of the 8344A>G mtDNA “MERRF” mutation. Neurology 80, 2049–2054 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Hopkins, S. E., Somoza, A. & Gilbert, D. L. Rare autosomal dominant POLG1 mutation in a family with metabolic strokes, posterior column spinal degeneration, and multi-endocrine disease. J. Child Neurol. 25, 752–756 (2010).

    Article  PubMed  Google Scholar 

  28. Garone, C. et al. MPV17 mutations causing adult-onset multisystemic disorder with multiple mitochondrial dna deletions. Arch. Neurol. 69, 1648–1651 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Janssen, G. M., Maassen, J. A. & van Den Ouweland, J. M. The diabetes-associated 3243 mutation in the mitochondrial tRNA(Leu(UUR)) gene causes severe mitochondrial dysfunction without a strong decrease in protein synthesis rate. J. Biol. Chem. 274, 29744–29748 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Maassen, J. A. et al. Mitochondrial diabetes and its lessons for common type 2 diabetes. Biochem. Soc. Trans. 34, 819–823 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. El-Hattab, A. W. et al. Glucose metabolism derangements in adults with the MELAS m.3243A>G mutation. Mitochondrion 18, 63–69 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Lindroos, M. M. et al. Mitochondrial diabetes is associated with insulin resistance in subcutaneous adipose tissue but not with increased liver fat content. J. Inherit. Metab. Dis. 34, 1205–1212 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Szendroedi, J. et al. Abnormal hepatic energy homeostasis in type 2 diabetes. Hepatology 50, 1079–1086 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Guillausseau, P. J. et al. Maternally inherited diabetes and deafness: a multicenter study. Ann. Intern. Med. 134, 721–728 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Rötig, A. et al. Pearson's marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy. J. Clin. Invest. 86, 1601–1608 (1990).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Williams, T. B. et al. Pearson syndrome: unique endocrine manifestations including neonatal diabetes and adrenal insufficiency. Mol. Genet. Metab. 106, 104–107 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Superti-Furga, A. et al. Pearson bone marrow-pancreas syndrome with insulin-dependent diabetes, progressive renal tubulopathy, organic aciduria and elevated fetal haemoglobin caused by deletion and duplication of mitochondrial DNA. Eur. J. Pediatr. 152, 44–50 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Morikawa, Y. et al. Pearson's marrow/pancreas syndrome: a histological and genetic study. Virchows Arch. A Pathol. Anat. Histopathol. 423, 227–231 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. Franzese, A., Del Giudice, E., Santoro, L., De Filippo, G. & Argenziano, A. Diabetes mellitus in Kearns-Sayre syndrome: a case with a 10-year follow-up. Diabetes Res. Clin. Pract. 30, 233–235 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Ho, J., Pacaud, D., Rakic, M. & Khan, A. Diabetes in pediatric patients with Kearns-Sayre syndrome: clinical presentation of 2 cases and a review of pathophysiology. Can. J. Diabetes 38, 225–228 (2014).

    Article  PubMed  Google Scholar 

  41. Yatsuga, S. et al. MELAS: a nationwide prospective cohort study of 96 patients in Japan. Biochim. Biophys. Acta 1820, 619–624 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Isotani, H. et al. Hypoparathyroidism and insulin-dependent diabetes mellitus in a patient with Kearns-Sayre syndrome harbouring a mitochondrial DNA deletion. Clin. Endocrinol. (Oxf.) 45, 637–641 (1996).

    Article  CAS  Google Scholar 

  43. Guillausseau, P. J. et al. Heterogeneity of diabetes phenotype in patients with 3243 bp mutation of mitochondrial DNA (Maternally Inherited Diabetes and Deafness or MIDD). Diabetes Metab. 30, 181–186 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. van Essen, E. H. et al. HLA-DQ polymorphism and degree of heteroplasmy of the A3243G mitochondrial DNA mutation in maternally inherited diabetes and deafness. Diabet. Med. 17, 841–847 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Majamaa-Voltti, K., Peuhkurinen, K., Kortelainen, M. L., Hassinen, I. E. & Majamaa, K. Cardiac abnormalities in patients with mitochondrial DNA mutation 3243A>G. BMC Cardiovasc. Disord. 2, 12 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Momiyama, Y. et al. Cardiac autonomic nervous dysfunction in diabetic patients with a mitochondrial DNA mutation: assessment by heart rate variability. Diabetes Care 25, 2308–2313 (2002).

    Article  PubMed  Google Scholar 

  47. Momiyama, Y. et al. Left ventricular hypertrophy and diastolic dysfunction in mitochondrial diabetes. Diabetes Care 24, 604–605 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Wahbi, K. et al. Long-term cardiac prognosis and risk stratification in 260 adults presenting with mitochondrial diseases. Eur. Heart J. 36, 2886–2860 (2015).

    Article  PubMed  Google Scholar 

  49. Ghosh, S. et al. The thiazolidinedione pioglitazone alters mitochondrial function in human neuron-like cells. Mol. Pharmacol. 71, 1695–1702 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Brunmair, B. et al. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53, 1052–1059 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Wolny, S., McFarland, R., Chinnery, P. & Cheetham, T. Abnormal growth in mitochondrial disease. Acta Paediatr. 98, 553–554 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Pitceathly, R. D. et al. NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease. Cell Rep. 3, 1795–1805 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Pitceathly, R. D. et al. COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood. JAMA Neurol. 70, 1556–1561 (2013).

    PubMed  Google Scholar 

  54. Wedatilake, Y. et al. SURF1 deficiency: a multi-centre natural history study. Orphanet J. Rare Dis. 8, 96 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Debray, F. G. et al. LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency. J. Med. Genet. 48, 183–189 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Berenberg, R. A. et al. Lumping or splitting? “Ophthalmoplegia-plus” or Kearns-Sayre syndrome? Ann. Neurol. 1, 37–54 (1977).

    Article  CAS  PubMed  Google Scholar 

  57. Harvey, J. N. & Barnett, D. Endocrine dysfunction in Kearns-Sayre syndrome. Clin. Endocrinol. (Oxf.) 37, 97–103 (1992).

    Article  CAS  Google Scholar 

  58. Matsuzaki, M., Izumi, T., Shishikura, K., Suzuki, H. & Hirayama, Y. Hypothalamic growth hormone deficiency and supplementary GH therapy in two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Neuropediatrics 33, 271–273 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Joko, T. et al. A case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes associated with diabetes mellitus and hypothalamo-pituitary dysfunction. Endocr. J. 44, 805–809 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Matsuzaki, M. et al. [Hypothalamic GH Deficiency and gelastic seizures in a 10-year-old girl with MELAS]. No To Hattatsu 23, 411–416 (in Japanese) (1991).

    CAS  PubMed  Google Scholar 

  61. Yorifuji, T. et al. Nephropathy and growth hormone deficiency in a patient with mitochondrial tRNA(Leu(UUR)) mutation. J. Med. Genet. 33, 621–622 (1996).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Balestri, P. & Grosso, S. Endocrine disorders in two sisters affected by MELAS syndrome. J. Child Neurol. 15, 755–758 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Berio, A. & Piazzi, A. Multiple endocrinopathies (growth hormone deficiency, autoimmune hypothyroidism and diabetes mellitus) in Kearns-Sayre syndrome. Pediatr. Med. Chir. 35, 137–140 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Obara-Moszynska, M. et al. A novel mitochondrial DNA deletion in a patient with Kearns-Sayre syndrome: a late-onset of the fatal cardiac conduction deficit and cardiomyopathy accompanying long-term rGH treatment. BMC Pediatr. 13, 27 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Cassandrini, D. et al. Mitochondrial DNA deletion in a child with mitochondrial encephalomyopathy, growth hormone deficiency, and hypoparathyroidism. J. Child Neurol. 21, 983–985 (2006).

    Article  PubMed  Google Scholar 

  66. Gucuyener, K., Seyrantepe, V., Topaloglu, H. & Ozguc, M. Mitochondrial deletion in a boy with growth hormone deficiency mimicking cerebral palsy. J. Inherit. Metab. Dis. 21, 173–174 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Rocha, V., Rocha, D., Santos, H. & Marques, J. S. Growth hormone deficiency in a patient with mitochondrial disease. J. Pediatr. Endocrinol. Metab. 28, 1003–1004 (2015).

    Article  PubMed  Google Scholar 

  68. Burns, E. C., Preece, M. A., Cameron, N. & Tanner, J. M. Growth hormone deficiency in mitochondrial cytopathy. Acta Paediatr. Scand. 71, 693–697 (1982).

    Article  CAS  PubMed  Google Scholar 

  69. Romano, S. et al. Variable outcome of growth hormone administration in respiratory chain deficiency. Mol. Genet. Metab. 93, 195–199 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Schwartzentruber, J. et al. Mutation in the nuclear-encoded mitochondrial isoleucyl-tRNA synthetase IARS2 in patients with cataracts, growth hormone deficiency with short stature, partial sensorineural deafness, and peripheral neuropathy or with Leigh syndrome. Hum. Mutat. 35, 1285–1289 (2014).

    CAS  PubMed  Google Scholar 

  71. Haack, T. B. et al. Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening. Mol. Genet. Metab. 111, 342–352 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Imagawa, E. et al. Homozygous p. V116* mutation in C12orf65 results in Leigh syndrome. J. Neurol. Neurosurg. Psychiatry 87, 212–216 (2016).

    Article  PubMed  Google Scholar 

  73. Barberi, S., Bozzola, E., Berardinelli, A., Meazza, C. & Bozzola, M. Long-term growth hormone therapy in mitochondrial cytopathy. Horm. Res. 62, 103–106 (2004).

    CAS  PubMed  Google Scholar 

  74. Berio, A. & Piazzi, A. [Kearns-Sayre syndrome with GH deficiency]. Pediatr. Med. Chir. 22, 43–46 (in Italian) (2000).

    CAS  PubMed  Google Scholar 

  75. Yau, E. K., Chan, K. Y., Au, K. M., Chow, T. C. & Chan, Y. W. A novel mitochondrial DNA deletion in a Chinese girl with Kearns-Sayre syndrome. Hong Kong Med. J. 15, 374–377 (2009).

    PubMed  Google Scholar 

  76. Achermann, J. C., Ozisik, G., Meeks, J. J. & Jameson, J. L. Genetic causes of human reproductive disease. J. Clin. Endocrinol. Metab. 87, 2447–2454 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Miller, W. L. & Bose, H. S. Early steps in steroidogenesis: intracellular cholesterol trafficking. J. Lipid Res. 52, 2111–2135 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Chen, C. M. & Huang, C. C. Gonadal dysfunction in mitochondrial encephalomyopathies. Eur. Neurol. 35, 281–286 (1995).

    Article  CAS  PubMed  Google Scholar 

  79. Chen, C. M. et al. Hypothalamic amenorrhea in a case of mitochondrial encephalomyopathy. J. Formos. Med. Assoc. 91, 1195–1199 (1992).

    CAS  PubMed  Google Scholar 

  80. Carod-Artal, F. J. et al. Cognitive dysfunction and hypogonadotrophic hypogonadism in a Brazilian patient with mitochondrial neurogastrointestinal encephalomyopathy and a novel ECGF1 mutation. Eur. J. Neurol. 14, 581–585 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Ohkoshi, N., Ishii, A., Shiraiwa, N., Shoji, S. & Yoshizawa, K. Dysfunction of the hypothalamic-pituitary system in mitochondrial encephalomyopathies. J. Med. 29, 13–29 (1998).

    CAS  PubMed  Google Scholar 

  82. Lonnqvist, T., Paetau, A., Valanne, L. & Pihko, H. Recessive twinkle mutations cause severe epileptic encephalopathy. Brain 132, 1553–1562 (2009).

    Article  PubMed  Google Scholar 

  83. Luoma, P. et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364, 875–882 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Pagnamenta, A. T. et al. Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum. Reprod. 21, 2467–2473 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Blok, M. J. et al. The unfolding clinical spectrum of POLG mutations. J. Med. Genet. 46, 776–785 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Kalkan, I. H. et al. A novel finding in MNGIE (mitochondrial neurogastrointestinal encephalomyopathy): hypergonadotropic hypogonadism. Hormones (Athens) 11, 377–379 (2012).

    Article  Google Scholar 

  87. Gironi, M. et al. Late-onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency. Neurology 62, 818–820 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Menezes, M. J. 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).

    Article  CAS  PubMed  Google Scholar 

  89. Dallabona, C. et al. Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology 82, 2063–2071 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Duncan, A. J., Knight, J. A., Costello, H., Conway, G. S. & Rahman, S. POLG mutations and age at menopause. Hum. Reprod. 27, 2243–2244 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Tong, Z. B. et al. Five mutations of mitochondrial DNA polymerase-gamma (POLG) are not a prevalent etiology for spontaneous 46,XX primary ovarian insufficiency. Fertil. Steril. 94, 2932–2934 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Suganuma, N., Kitagawa, T., Nawa, A. & Tomoda, Y. Human ovarian aging and mitochondrial DNA deletion. Horm. Res. 39 (Suppl. 1), 16–21 (1993).

    Article  CAS  PubMed  Google Scholar 

  93. May-Panloup, P., Chretien, M. F., Malthiery, Y. & Reynier, P. Mitochondrial DNA in the oocyte and the developing embryo. Curr. Top. Dev. Biol. 77, 51–83 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Bentov, Y. & Casper, R. F. The aging oocyte—can mitochondrial function be improved? Fertil. Steril. 99, 18–22 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Zhen, X. et al. Increased incidence of mitochondrial cytochrome C oxidase 1 gene mutations in patients with primary ovarian insufficiency. PLoS ONE 10, e0132610 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Mukai, M. et al. [Familial progressive external opthalmoplegia, parkinsonism and polyneuropathy associated with POLG1 mutation]. Rinsho Shinkeigaku 54, 417–422 (2014)

    Article  PubMed  Google Scholar 

  97. Pierce, S. B. et al. Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc. Natl. Acad. Sci. USA 108, 6543–6548 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Demain, L. A. et al. Expanding the genotypic spectrum of perrault syndrome. Clin. Genet. http://dx.doi.org/10.1111/cge.12776 (2016).

  99. Morino, H. et al. Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features. Neurology 83, 2054–2061 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Newman, W. G., Friedman, T. B. & Conway, G. S. Perrault Syndrome in GeneReviews (eds Pagon, R. A. et al.) (University of Washington, Seattle, 1993–2016).

  101. Pierce, S. B. et al. Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. Am. J. Hum. Genet. 92, 614–620 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Jenkinson, E. M. et al. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am. J. Hum. Genet. 92, 605–613 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Ahmed, S. et al. Exome analysis identified a novel missense mutation in the CLPP gene in a consanguineous Saudi family expanding the clinical spectrum of Perrault Syndrome type-3. J. Neurol. Sci. 353, 149–154 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. Aknin-Seifer, I. E. et al. Is the CAG repeat of mitochondrial DNA polymerase gamma (POLG) associated with male infertility? A multi-centre French study. Hum. Reprod. 20, 736–740 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Poongothai, J. Mitochondrial DNA polymerase gamma gene polymorphism is not associated with male infertility. J. Assist. Reprod. Genet. 30, 1109–1114 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Brusco, A. et al. The polymorphic polyglutamine repeat in the mitochondrial DNA polymerase gamma gene is not associated with oligozoospermia. J. Endocrinol. Invest. 29, 1–4 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Artuch, R. et al. Multiple endocrine involvement in two pediatric patients with Kearns-Sayre syndrome. Horm. Res. 50, 99–104 (1998).

    CAS  PubMed  Google Scholar 

  108. Boles, R. G., Roe, T., Senadheera, D., Mahnovski, V. & Wong, L. J. Mitochondrial DNA deletion with Kearns Sayre syndrome in a child with Addison disease. Eur. J. Pediatr. 157, 643–647 (1998).

    Article  CAS  PubMed  Google Scholar 

  109. Tzoufi, M. et al. A rare case report of simultaneous presentation of myopathy, Addison's disease, primary hypoparathyroidism, and Fanconi syndrome in a child diagnosed with Kearns-Sayre syndrome. Eur. J. Pediatr. 172, 557–561 (2013).

    Article  PubMed  Google Scholar 

  110. Duran, G. P. et al. Large mitochondrial DNA deletion in an infant with Addison disease. JIMD Rep. 3, 5–9 (2012).

    Article  PubMed  Google Scholar 

  111. Ribes, A. et al. Pearson syndrome: altered tricarboxylic acid and urea-cycle metabolites, adrenal insufficiency and corneal opacities. J. Inherit. Metab. Dis. 16, 537–540 (1993).

    Article  CAS  PubMed  Google Scholar 

  112. Calderwood, L., Holm, I. A., Teot, L. A. & Anselm, I. Adrenal insufficiency in mitochondrial disease: a rare case of GFER-related mitochondrial encephalomyopathy and review of the literature. J. Child Neurol. 31, 190–194 (2015).

    Article  PubMed  Google Scholar 

  113. Afroze, B., Amjad, N., Ibrahim, S. H., Humayun, K. N. & Yakob, Y. Adrenal insufficiency in a child with MELAS syndrome. Brain Dev. 36, 924–927 (2014).

    Article  PubMed  Google Scholar 

  114. Papadopoulos, V. & Miller, W. L. Role of mitochondria in steroidogenesis.. Best Pract. Res. Clin. Endocrinol. Metab. 26, 771–790 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Guran, T. et al. Rare causes of primary adrenal insufficiency: genetic and clinical characterization of a large nationwide cohort. J. Clin. Endocrinol. Metab. 101, 284–292 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Meimaridou, E. et al. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat. Genet. 44, 740–742 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Prasad, R. et al. Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J. Clin. Endocrinol. Metab. 99, E1556–E1563 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Prasad, R., Kowalczyk, J. C., Meimaridou, E., Storr, H. L. & Metherell, L. A. Oxidative stress and adrenocortical insufficiency. J. Endocrinol. 221, R63–R73 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Sugiana, C. et al. Mutation of C20orf7 disrupts complex I assembly and causes lethal neonatal mitochondrial disease. Am. J. Hum. Genet. 83, 468–478 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Kasiviswanathan, R. & Copeland, W. C. Biochemical analysis of the G517V POLG variant reveals wild-type like activity. Mitochondrion 11, 929–934 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Nicolino, M. et al. Identification of a large-scale mitochondrial deoxyribonucleic acid deletion in endocrinopathies and deafness: report of two unrelated cases with diabetes mellitus and adrenal insufficiency, respectively. J. Clin. Endocrinol. Metab. 82, 3063–3067 (1997).

    CAS  PubMed  Google Scholar 

  122. Sasaki, H., Kuzuhara, S., Kanazawa, I., Nakanishi, T. & Ogata, T. Myoclonus, cerebellar disorder, neuropathy, mitochondrial myopathy, and ACTH deficiency. Neurology 33, 1288–1293 (1983).

    Article  CAS  PubMed  Google Scholar 

  123. Bordarier, C., Duyckaerts, C., Robain, O., Ponsot, G. & Laplane, D. Kearns-Sayre syndrome. Two clinico-pathological cases. Neuropediatrics 21, 106–109 (1990).

    Article  CAS  PubMed  Google Scholar 

  124. Horwitz, S. J. & Roessmann, U. Kearns-Sayre syndrome with hypoparathyroidism. Ann. Neurol. 3, 513–518 (1978).

    Article  CAS  PubMed  Google Scholar 

  125. Wilichowski, E. et al. Hypoparathyroidism and deafness associated with pleioplasmic large scale rearrangements of the mitochondrial DNA: a clinical and molecular genetic study of four children with Kearns-Sayre syndrome. Pediatr. Res. 41, 193–200 (1997).

    Article  CAS  PubMed  Google Scholar 

  126. Ashrafzadeh, F., Ghaemi, N., Akhondian, J., Beiraghi Toosi, M. & Elmi, S. Hypoparathyroidism as the first manifestation of Kearns-Sayre syndrome: a case report. Iran. J. Child Neurol. 7, 53–57 (2013).

    PubMed  PubMed Central  Google Scholar 

  127. Tengan, C. H. et al. Mitochondrial encephalomyopathy and hypoparathyroidism associated with a duplication and a deletion of mitochondrial deoxyribonucleic acid. J. Clin. Endocrinol. Metab. 83, 125–129 (1998).

    CAS  PubMed  Google Scholar 

  128. Lee, Y. S. et al. Mitochondrial tubulopathy: the many faces of mitochondrial disorders. Pediatr. Nephrol. 16, 710–712 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Goto, Y. et al. Renal tubular involvement mimicking Bartter syndrome in a patient with Kearns-Sayre syndrome. J. Pediatr. 116, 904–910 (1990).

    Article  CAS  PubMed  Google Scholar 

  130. Emma, F., Bertini, E., Salviati, L. & Montini, G. Renal involvement in mitochondrial cytopathies. Pediatr. Nephrol. 27, 539–550 (2012).

    Article  PubMed  Google Scholar 

  131. Agus, Z. S. Hypomagnesemia. J. Am. Soc. Nephrol. 10, 1616–1622 (1999).

    CAS  PubMed  Google Scholar 

  132. Katsanos, K. H., Elisaf, M., Bairaktari, E. & Tsianos, E. V. Severe hypomagnesemia and hypoparathyroidism in Kearns-Sayre syndrome. Am. J. Nephrol. 21, 150–153 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Tanaka, K. et al. Diabetes mellitus, deafness, muscle weakness and hypocalcemia in a patient with an A3243G mutation of the mitochondrial DNA. Intern. Med. 39, 249–252 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Toppet, M., Telerman-Toppet, N., Szliwowski, H. B., Vainsel, M. & Coers, C. Oculocraniosomatic neuromuscular disease with hypoparathyroidism. Am. J. Dis. Child 131, 437–441 (1977).

    CAS  PubMed  Google Scholar 

  135. Pfeffer, G., Sirrs, S., Wade, N. K. & Mezei, M. M. Multisystem disorder in late-onset chronic progressive external ophthalmoplegia. Can. J. Neurol. Sci. 38, 119–123 (2011).

    Article  PubMed  Google Scholar 

  136. Hu, H. et al. Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness. Ann. Clin. Transl. Neurol. 1, 1024–1035 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Canaris, G. J., Tape, T. G. & Wigton, R. S. Thyroid disease awareness is associated with high rates of identifying subjects with previously undiagnosed thyroid dysfunction. BMC Public Health 13, 351 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank A. Khabbush (Genetics and Genomic Medicine Programme, University College London Great Ormond Street Institute of Child Health, London, UK) for assistance with the artwork. S.R. is supported by Great Ormond Street Hospital Children's Charity (research leadership grant V1260) and currently receives research grant funding from The Wellcome Trust, The Lily Foundation, and Vitaflo International Ltd. J.C.A. is a Wellcome Trust Senior Research Fellow in Clinical Science [098513]. J.C.A., M.T.D. and S.R. all receive support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London, UK.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shamima Rahman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chow, J., Rahman, J., Achermann, J. et al. Mitochondrial disease and endocrine dysfunction. Nat Rev Endocrinol 13, 92–104 (2017). https://doi.org/10.1038/nrendo.2016.151

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2016.151

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing