Endocrine Dysfunction in Primary Mitochondrial Diseases

Rachel Varughese and Shamima Rahman
Endocrine Reviews, First published online February 1, 2025, bnaf002
https://doi.org/10.1210/endrev/bnaf002

Abstract

Primary mitochondrial disorders (PMD) are genetic disorders affecting the structure or function of the mitochondrion. Mitochondrial functions are diverse, including energy production, ion homeostasis, reactive oxygen species regulation, antioxidant defense, and biosynthetic responsibilities, notably including steroidogenesis. Mitochondria provide the energy to drive intracellular production and extracellular secretion of all hormones. The understanding of the endocrine consequences of PMD is key to timely identification of both endocrine complications in PMD patients, and PMD presenting primarily with endocrine disease. This is a narrative review on the endocrine manifestations of PMD, underlying disease mechanisms, and current and emerging approaches to diagnosing and treating these complex disorders. Diabetes is the most frequent endocrine manifestation of PMD, but growth hormone deficiency, adrenal insufficiency, hypogonadism, and parathyroid dysfunction may occur. Despite the intricate involvement of the thyroid gland in metabolic regulation, there is little evidence for a causal relationship between thyroid dysfunction and PMD. In conclusion, endocrine dysfunction is observed in PMD with varying incidence depending on the specific mitochondrial disorder and the endocrine organ in question. Diagnosis of PMD in a patient with endocrine-presenting features requires a high level of clinical suspicion, particularly when apparently unrelated comorbidities co-exist. Similarly, endocrine pathology may be subtle in patients with known PMD, and thorough consideration must be given to ensure timely diagnosis and treatment. The scope for novel therapeutics for this group of devastating conditions is enormous; however, several challenges remain to be overcome before hopes of curative treatments can be brought into clinical practice.

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