Diabetes Associated With Maternally Inherited Diabetes and Deafness (MIDD): From Pathogenic Variant to Phenotype

Maternally inherited diabetes and deafness (MIDD) is a monogenic mitochondrial disorder caused by a pathogenic variant in the MT-TL1 gene encoding 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 β-cell function that seems more likely to occur in the presence of high skeletal muscle heteroplasmy and moderate β-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 signaling. mTORC1 hyperactivity contributes to insulin resistance and β-cell dysfunction and to an increased load of the m.3243A>G phenotypic variant. Abnormal mitochondrial signaling affects the nuclear epigenome and influences MIDD phenotype. We highlight evidence that, despite being an apparent pathogenic factor, 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 contribute. A better understanding of the mechanisms leading to MIDD will help inform novel management strategies for this form of diabetes. Article Highlights Maternally inherited diabetes and deafness (MIDD) is a mitochondrial disorder characterized primarily by hearing impairment and diabetes. m.3243A>G, the most common phenotypic variant, causes a complex rewiring of the cell with discontinuous remodeling of both mitochondrial and nuclear genome expressions. We propose that MIDD depends on a combination of insulin resistance and impaired β-cell function that occurs in the presence of high skeletal muscle heteroplasmy (approximately ≥60%) and more moderate cell heteroplasmy (∼25%–72%) for m.3243A>G. Understanding the complex mechanisms of MIDD is necessary to develop disease-specific management guidelines that are presently lacking.

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