In a review paper in Endocrine Reviews, Rachel Varughese and Shamima Rahman of University College London describe the effects of primary mitochondrial disease on the endocrine system and how these diseases can be diagnosed and treated.

Mitochondria provide the energy for the production and export of many cellular products. Mutations that affect mitochondrial function can disrupt the production of key molecules, including endocrine hormones. The result might be diabetes, growth hormone deficiency, adrenal insufficiency, hypogonadism, and parathyroid dysfunction. In fact, the authors suggest that the possibility of underlying mitochondrial dysfunction should be considered in all hormonal diseases. Thus, understanding how the mitochondria are involved in those diseases is critical.

Primary mitochondrial disorders (PMDs) are genetic disorders that affect the structure or function of the mitochondria. Because mitochondria are so intimately involved with multiple cellular functions, mitochondrial mutations can manifest in many disorders. The mutation can occur in either the nuclear or mitochondrial genome.

Varughese and Rahman provide an extensive review of how mitochondria can be damaged and of the diseases that can result. They conclude by noting that clinicians should be suspicious of a PMD for any patient who has an atypical presentation or seemingly unrelated comorbidities. The treatment of PMDs can be complex and quite different than the “normal” treatment for a particular endocrine manifestation.

A conversation with Rahman and Varughese

MitoWorld: Since there is no cure for PMDs right now, are clinicians left with treating the symptoms?

Rahman: Yes, symptomatic management is the mainstay of managing PMDs at present. This means being vigilant and monitoring for known complications of the disease and acting promptly with symptomatic measures when these complications arise.

MitoWorld: You seem to be suggesting that clinicians should be aware of multiple, possible unusual combinations of symptoms that might indicate a PMD. Are there key diseases other than diabetes that should raise suspicion?

Rahman. Table 6 in our paper gives several examples of combinations of symptoms that should arouse suspicion of an underlying PMD. For example, the combination of adrenal insufficiency or growth hormone deficiency with progressive external ophthalmoplegia, pigmentary retinopathy and heart block should alert the clinician to the possibility of Kearns-Sayre syndrome, while the combination of premature ovarian insufficiency and sensorineural hearing loss is suspicious of Perrault syndrome.

MitoWorld: What are the most promising treatments that you are aware of?

Rahman: Unfortunately, there are no disease-modifying therapies that are licensed for PMDs. Many treatments are in development at the preclinical stages, including pharmacological and genetic approaches. Currently, genetic approaches seem more promising as strategies to provide personalized tailored curative treatments, but are not yet available for PMDs, with the exception of Leber Hereditary Optic Neuropathy.

MitoWorld: What interested you in mitochondrial in the first place?

Rahman: I first began caring for patients with mitochondrial diseases as a junior doctor (paediatric trainee) in the early 1990s. Deeply moved by the challenges faced by affected patients and their families, I have devoted my career to improving the diagnosis and management of these conditions.

Varughese: I am a paediatric endocrinologist. As a paediatrician, I was drawn to endocrinology by the opportunity to make lasting impacts on children’s growth and development through targeted, evidence-based care. My interest in mitochondrial disease emerged from seeing its intricate interplay with multiple organ systems, including endocrine function. Writing this article was a way to bridge both interests, aiming to improve both early recognition of endocrine issues in affected children and the identification of underlying mitochondrial disease in patients with atypical constellations of symptoms.

 

Reference

Varughese R, Rahman S (2025) Endocrine dysfunction in primary mitochondrial diseases. Endocrine Reviews 46: 376–396.