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
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
Open Access articles citing this article.
Reviews in Endocrine and Metabolic Disorders Open Access 18 October 2022
Italian Journal of Pediatrics Open Access 17 October 2022
Current Neurology and Neuroscience Reports Open Access 05 May 2021
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Chinnery, P. F. Mitochondrial disorders overview in GeneReviews (eds Pagon, R. A. et al.) (University of Washington, Seattle, 1993–2016).
Thorburn, D. R. Mitochondrial disorders: prevalence, myths and advances. J. Inherit. Metab. Dis. 27, 349–362 (2004).
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).
Stark, R. & Roden, M. ESCI Award 2006. Mitochondrial function and endocrine diseases. Eur. J. Clin. Invest. 37, 236–248 (2007).
Miller, W. L. Steroid hormone synthesis in mitochondria. Mol. Cell. Endocrinol. 379, 62–73 (2013).
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).
Kohda, M. et al. A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet. 12, e1005679 (2016).
Payne, B. A. et al. Universal heteroplasmy of human mitochondrial DNA. Hum. Mol. Genet. 22, 384–390 (2013).
Schaefer, A. M., Walker, M., Turnbull, D. M. & Taylor, R. W. Endocrine disorders in mitochondrial disease. Mol. Cell. Endocrinol. 379, 2–11 (2013).
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).
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).
Sacconi, S. et al. A functionally dominant mitochondrial DNA mutation. Hum. Mol. Genet. 17, 1814–1820 (2008).
Munnich, A. et al. Clinical presentation of mitochondrial disorders in childhood. J. Inherit. Metab. Dis. 19, 521–527 (1996).
Broomfield, A. et al. Paediatric single mitochondrial DNA deletion disorders: an overlapping spectrum of disease. J. Inherit. Metab. Dis. 38, 445–457 (2015).
Quade, A., Zierz, S. & Klingmuller, D. Endocrine abnormalities in mitochondrial myopathy with external ophthalmoplegia. Clin. Investig. 70, 396–402 (1992).
DiMauro, S. & Hirano, M. Mitochondrial DNA Deletion Syndromes in GeneReviews (eds Pagon, R. A. et al.) (University of Washington, Seattle, 1993–2016).
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).
Maechler, P. Mitochondrial function and insulin secretion. Mol. Cell. Endocrinol. 379, 12–18 (2013).
Maassen, J. A. et al. Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes 53 (Suppl. 1), S103–S109 (2004).
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).
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).
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).
Kishimoto, M. et al. Diabetes mellitus carrying a mutation in the mitochondrial tRNA(Leu(UUR)) gene. Diabetologia 38, 193–200 (1995).
Karaa, A. & Goldstein, A. The spectrum of clinical presentation, diagnosis, and management of mitochondrial forms of diabetes. Pediatr. Diabetes 16, 1–9 (2015).
Whittaker, R. G. et al. Prevalence and progression of diabetes in mitochondrial disease. Diabetologia 50, 2085–2089 (2007).
Mancuso, M. et al. Phenotypic heterogeneity of the 8344A>G mtDNA “MERRF” mutation. Neurology 80, 2049–2054 (2013).
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).
Garone, C. et al. MPV17 mutations causing adult-onset multisystemic disorder with multiple mitochondrial dna deletions. Arch. Neurol. 69, 1648–1651 (2012).
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).
Maassen, J. A. et al. Mitochondrial diabetes and its lessons for common type 2 diabetes. Biochem. Soc. Trans. 34, 819–823 (2006).
El-Hattab, A. W. et al. Glucose metabolism derangements in adults with the MELAS m.3243A>G mutation. Mitochondrion 18, 63–69 (2014).
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).
Szendroedi, J. et al. Abnormal hepatic energy homeostasis in type 2 diabetes. Hepatology 50, 1079–1086 (2009).
Guillausseau, P. J. et al. Maternally inherited diabetes and deafness: a multicenter study. Ann. Intern. Med. 134, 721–728 (2001).
Rötig, A. et al. Pearson's marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy. J. Clin. Invest. 86, 1601–1608 (1990).
Williams, T. B. et al. Pearson syndrome: unique endocrine manifestations including neonatal diabetes and adrenal insufficiency. Mol. Genet. Metab. 106, 104–107 (2012).
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).
Morikawa, Y. et al. Pearson's marrow/pancreas syndrome: a histological and genetic study. Virchows Arch. A Pathol. Anat. Histopathol. 423, 227–231 (1993).
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).
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).
Yatsuga, S. et al. MELAS: a nationwide prospective cohort study of 96 patients in Japan. Biochim. Biophys. Acta 1820, 619–624 (2012).
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).
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).
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).
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).
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).
Momiyama, Y. et al. Left ventricular hypertrophy and diastolic dysfunction in mitochondrial diabetes. Diabetes Care 24, 604–605 (2001).
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).
Ghosh, S. et al. The thiazolidinedione pioglitazone alters mitochondrial function in human neuron-like cells. Mol. Pharmacol. 71, 1695–1702 (2007).
Brunmair, B. et al. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53, 1052–1059 (2004).
Wolny, S., McFarland, R., Chinnery, P. & Cheetham, T. Abnormal growth in mitochondrial disease. Acta Paediatr. 98, 553–554 (2009).
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).
Pitceathly, R. D. et al. COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood. JAMA Neurol. 70, 1556–1561 (2013).
Wedatilake, Y. et al. SURF1 deficiency: a multi-centre natural history study. Orphanet J. Rare Dis. 8, 96 (2013).
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).
Berenberg, R. A. et al. Lumping or splitting? “Ophthalmoplegia-plus” or Kearns-Sayre syndrome? Ann. Neurol. 1, 37–54 (1977).
Harvey, J. N. & Barnett, D. Endocrine dysfunction in Kearns-Sayre syndrome. Clin. Endocrinol. (Oxf.) 37, 97–103 (1992).
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).
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).
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).
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).
Balestri, P. & Grosso, S. Endocrine disorders in two sisters affected by MELAS syndrome. J. Child Neurol. 15, 755–758 (2000).
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).
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).
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).
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).
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).
Burns, E. C., Preece, M. A., Cameron, N. & Tanner, J. M. Growth hormone deficiency in mitochondrial cytopathy. Acta Paediatr. Scand. 71, 693–697 (1982).
Romano, S. et al. Variable outcome of growth hormone administration in respiratory chain deficiency. Mol. Genet. Metab. 93, 195–199 (2008).
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).
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).
Imagawa, E. et al. Homozygous p. V116* mutation in C12orf65 results in Leigh syndrome. J. Neurol. Neurosurg. Psychiatry 87, 212–216 (2016).
Barberi, S., Bozzola, E., Berardinelli, A., Meazza, C. & Bozzola, M. Long-term growth hormone therapy in mitochondrial cytopathy. Horm. Res. 62, 103–106 (2004).
Berio, A. & Piazzi, A. [Kearns-Sayre syndrome with GH deficiency]. Pediatr. Med. Chir. 22, 43–46 (in Italian) (2000).
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).
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).
Miller, W. L. & Bose, H. S. Early steps in steroidogenesis: intracellular cholesterol trafficking. J. Lipid Res. 52, 2111–2135 (2011).
Chen, C. M. & Huang, C. C. Gonadal dysfunction in mitochondrial encephalomyopathies. Eur. Neurol. 35, 281–286 (1995).
Chen, C. M. et al. Hypothalamic amenorrhea in a case of mitochondrial encephalomyopathy. J. Formos. Med. Assoc. 91, 1195–1199 (1992).
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).
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).
Lonnqvist, T., Paetau, A., Valanne, L. & Pihko, H. Recessive twinkle mutations cause severe epileptic encephalopathy. Brain 132, 1553–1562 (2009).
Luoma, P. et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364, 875–882 (2004).
Pagnamenta, A. T. et al. Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum. Reprod. 21, 2467–2473 (2006).
Blok, M. J. et al. The unfolding clinical spectrum of POLG mutations. J. Med. Genet. 46, 776–785 (2009).
Kalkan, I. H. et al. A novel finding in MNGIE (mitochondrial neurogastrointestinal encephalomyopathy): hypergonadotropic hypogonadism. Hormones (Athens) 11, 377–379 (2012).
Gironi, M. et al. Late-onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency. Neurology 62, 818–820 (2004).
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).
Dallabona, C. et al. Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology 82, 2063–2071 (2014).
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).
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).
Suganuma, N., Kitagawa, T., Nawa, A. & Tomoda, Y. Human ovarian aging and mitochondrial DNA deletion. Horm. Res. 39 (Suppl. 1), 16–21 (1993).
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).
Bentov, Y. & Casper, R. F. The aging oocyte—can mitochondrial function be improved? Fertil. Steril. 99, 18–22 (2013).
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).
Mukai, M. et al. [Familial progressive external opthalmoplegia, parkinsonism and polyneuropathy associated with POLG1 mutation]. Rinsho Shinkeigaku 54, 417–422 (2014)
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).
Demain, L. A. et al. Expanding the genotypic spectrum of perrault syndrome. Clin. Genet. http://dx.doi.org/10.1111/cge.12776 (2016).
Morino, H. et al. Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features. Neurology 83, 2054–2061 (2014).
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).
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).
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).
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).
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).
Poongothai, J. Mitochondrial DNA polymerase gamma gene polymorphism is not associated with male infertility. J. Assist. Reprod. Genet. 30, 1109–1114 (2013).
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).
Artuch, R. et al. Multiple endocrine involvement in two pediatric patients with Kearns-Sayre syndrome. Horm. Res. 50, 99–104 (1998).
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).
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).
Duran, G. P. et al. Large mitochondrial DNA deletion in an infant with Addison disease. JIMD Rep. 3, 5–9 (2012).
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).
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).
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).
Papadopoulos, V. & Miller, W. L. Role of mitochondria in steroidogenesis.. Best Pract. Res. Clin. Endocrinol. Metab. 26, 771–790 (2012).
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).
Meimaridou, E. et al. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat. Genet. 44, 740–742 (2012).
Prasad, R. et al. Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J. Clin. Endocrinol. Metab. 99, E1556–E1563 (2014).
Prasad, R., Kowalczyk, J. C., Meimaridou, E., Storr, H. L. & Metherell, L. A. Oxidative stress and adrenocortical insufficiency. J. Endocrinol. 221, R63–R73 (2014).
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).
Kasiviswanathan, R. & Copeland, W. C. Biochemical analysis of the G517V POLG variant reveals wild-type like activity. Mitochondrion 11, 929–934 (2011).
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).
Sasaki, H., Kuzuhara, S., Kanazawa, I., Nakanishi, T. & Ogata, T. Myoclonus, cerebellar disorder, neuropathy, mitochondrial myopathy, and ACTH deficiency. Neurology 33, 1288–1293 (1983).
Bordarier, C., Duyckaerts, C., Robain, O., Ponsot, G. & Laplane, D. Kearns-Sayre syndrome. Two clinico-pathological cases. Neuropediatrics 21, 106–109 (1990).
Horwitz, S. J. & Roessmann, U. Kearns-Sayre syndrome with hypoparathyroidism. Ann. Neurol. 3, 513–518 (1978).
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).
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).
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).
Lee, Y. S. et al. Mitochondrial tubulopathy: the many faces of mitochondrial disorders. Pediatr. Nephrol. 16, 710–712 (2001).
Goto, Y. et al. Renal tubular involvement mimicking Bartter syndrome in a patient with Kearns-Sayre syndrome. J. Pediatr. 116, 904–910 (1990).
Emma, F., Bertini, E., Salviati, L. & Montini, G. Renal involvement in mitochondrial cytopathies. Pediatr. Nephrol. 27, 539–550 (2012).
Agus, Z. S. Hypomagnesemia. J. Am. Soc. Nephrol. 10, 1616–1622 (1999).
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).
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).
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).
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).
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).
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).
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 . 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.
The authors declare no competing financial interests.
About this article
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
This article is cited by
Italian Journal of Pediatrics (2022)
Reviews in Endocrine and Metabolic Disorders (2022)
Current Neurology and Neuroscience Reports (2021)
Central precocious puberty may be a manifestation of endocrine dysfunction in pediatric patients with mitochondrial disease
European Journal of Pediatrics (2021)
Heart Failure Reviews (2021)