We were interested to read the article by Chanoine et al. (1) on the pathophysiological considerations of how the m.3243A>G variant may lead to diabetes in people with maternally inherited diabetes and deafness (MIDD). It has been suggested that diabetes in MIDD is due to a combination of insulin resistance and impaired β-cell function in high-lymphocyte m.3243A>G heteroplasmy but moderate β-cell heteroplasmy (1). In addition, it has been suggested that the mutation causes oxidative stress that disrupts the tricarboxylic cycle, leading to mTORC1 hyperactivity and alteration of mitochondrial retrograde signaling (1). Abnormal mTORC1 signaling could in turn contribute to insulin resistance and β-cell dysfunction by increasing the heteroplasmy rate and affecting the nuclear epigenome (1). The study is excellent, but some points should be discussed.
The first point is that hyperactivity of mTORC1 signaling is not essential to explain pancreatic involvement. Impaired function of complexes I, III, and IV may lead to decreased ATP production, and thus β-cell dysfunction, simply due to the reduced amount of available ATP produced by these cells and the associated increased oxidative stress. Although the mtDNA variant m.3243A>G causes oxidative stress that disrupts the tricarboxylic cycle, leading to mTORC1 hyperactivity, there is also mTORC1-independent activation of mitochondrial tricarboxylic cycle flux of acetyl-CoA through activation of pyruvate dehydrogenase via Rheb (2).
The second point is that, assuming that hyperactivity of mTORC1 signaling leads to increased heteroplasmy rates, one would expect high heteroplasmy rates or even homoplasmy rates in β-cells, which contradicts the authors' theory that heteroplasmy rates are only moderately increased in β-cells (1).
The third point is that the haplotype has not been considered as a phenotype-determining factor. Haplotypes are defined by groups of polymorphic changes that have been fixed in specific populations or groups of individuals (3). Since certain haplotypes predispose to diseases such as cardiomyopathy, Alzheimer's disease, dementia with Lewy bodies, or multiple sclerosis, it is conceivable that homoplasmic haplotypes also influence the phenotypic expression of the m.3243A>G variant. Another argument in favor of haplotypes determining the phenotype is that certain haplotypes confer positive traits, such as adaptation to cold climates (3).
The fourth point is that MIDD can manifest phenotypically with diabetes and deafness and, in most cases, as a multisystem disease like most syndromic and nonsyndromic mitochondrial disorders. In the case of MIDD, the multisystem involvement is referred to as MIDD plus. In addition to deafness and diabetes, phenotypic features of MIDD plus patients include cognitive impairment, epilepsy, cerebellar ataxia, ischemic stroke, maculopathy, retinopathy, cataract, hypothyroidism, hypogonadism, intestinal pseudo-obstruction, focal segmental glomerulosclerosis, renal insufficiency unrelated to diabetes, and myopathy (4,5). Consideration and diagnosis of multisystem involvement is crucial, as it may determine the extent of disease progression and outcome for these patients.
Overall, this interesting review has limitations that put the results and their interpretation into perspective. Addressing these limitations could strengthen the conclusions and reinforce the message of the study. Before the development of diabetes in m.3243A>G carriers is explained by hyperactive mTORC1 signaling, alternative pathophysiological explanations should be ruled out.
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Duality of Interest. No potential conflicts of interest relevant to this article were reported.
