Maternally inherited diabetes and deafness (MIDD) is a monogenic mitochondrial disorder caused by a pathogenic variant in the MT-TL1 gene encoding for a leucine transfer RNA. We propose a new hypothesis that explains how the MT-TL1 variant causes impaired glucose tolerance and diabetes in MIDD. We suggest that diabetes in MIDD primarily depends on a variable combination of insulin resistance and impaired beta cell function that seems more likely to occur in the presence of high skeletal muscle heteroplasmy and moderate beta cell heteroplasmy for m.3243A>G. The underlying genetic defect generates oxidative stress and disrupts the tricarboxylic acid cycle, leading to mTORC1 hyperactivity and modifying mitochondrial retrograde signalling. mTORC1 hyperactivity contributes to insulin resistance and beta cell dysfunction and to an increased load of the m.3243A>G phenotypic variant. Abnormal mitochondrial signalling affects the nuclear epigenome and influences MIDD phenotype. Despite being an apparent pathogenic factor, we highlight evidence showing that heteroplasmy in the blood and in tissues, does not fully explain the phenotypic variability of this condition, and that other factors, including mtDNA copy number, additional nuclear or mitochondrial variants, environmental factors and metabolic characteristics of the patient may be contributing factors. A better understanding of the mechanisms leading to MIDD diabetes will help inform novel management strategies for this form of diabetes.
