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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.

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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.

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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.

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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

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