Mitochondrial disease and endocrine dysfunction

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.

Genetic Screening in a Large Chinese Cohort of Childhood Onset Hypoparathyroidism by Next-Generation Sequencing Combined with TBX1-MLPA

“…First, we did not analyze mitochondrial DNA and new candidate genes (NEBL, HADHA, HADHB, and DHCR7) associated with hypoparathyroidism. (36)(37)(38)(39)(40)(41)(42)(43) However, mitochondrial disorders and new candidate gene defect-related symptoms were not seen in patients without mutations in our study. Second, immune-mediated HP was not fully excluded in our subjects, which may explain the majority of causes in patients without mutations, although it did not affect the genetic and clinical characteristics of patients with hereditary hypoparathyroidism.…”

“…Our study has some limitations. First, we did not analyze mitochondrial DNA and new candidate genes ( NEBL , HADHA , HADHB , and DHCR7 ) associated with hypoparathyroidism . However, mitochondrial disorders and new candidate gene defect–related symptoms were not seen in patients without mutations in our study.…”

Mitochondrial dysfunction and potential anticancer therapy

“…Mitochondria contain the rate‐limiting enzymes for pyrimidine and heme synthesis, oxidative phosphorylation (OXPHOS), free radical production and detoxification, cholesterol and neurotransmitter metabolism, and execution of the apoptotic program . Not surprisingly, a mitochondrial basis to illness ranges from neurological disorders, to diseases of the cardiovascular system, liver, kidney, diabetes, as well as DNA damage response (DDR) related cancer development and progression . Cumulatively called mitochondrial dysfunction (MDF), this term is now widely used in the literature and includes changes in mitochondrial morphology, loss of the mitochondrial membrane potential (∆Ψm), low oxygen consumption rate (OCR), misbalance between production and detoxifying of reactive oxygen (ROS) and reactive nitrogen (RNS) species, impaired protein traffic into mitochondria, altered expression of OXPHOS and electron transport chain (ETC) genes, decreased ATP production, abnormal Ca 2+ level, glutathione depletion, inhibition of ionic pumps, glutamate excitotoxicity, and other similar anomalies …”

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society

“…Recent reviews on the topic are available. 20,21 Diabetes mellitus has long been a well-recognized potential endocrine consequence of mitochondrial disease. 23 Clinical presentations suggestive of either "typical" Type I or II diabetes mellitus can both be caused by primary mitochondrial impairment (mitochondrial disease-associated diabetes mellitus).…”

“…Diabetes mellitus due to insulin insufficiency secondary to islet cell dysfunction or insulin resistance [17][18][19] , primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism and hypogonadism are also seen. 20,21 Patients with mitochondrial diseases may be chronically malnourished with deficiencies of both macro and micronutrients. Decreases in nutritional intake due to poor oral or enteral tolerance, in the setting of gastrointestinal (GI) dysmotility and paralytic ileus may further compromise nutrition in ill states.…”