Diabetes is associated with impaired glucose metabolism in the presence of excess insulin. Glucose and fatty acids provide reducing equivalents to mitochondria to generate energy, and studies have reported mitochondrial dysfunction in type II diabetes patients. If mitochondrial dysfunction can cause diabetes, then we hypothesized that increased mitochondrial metabolism should render animals resistant to diabetes. This was confirmed in mice in which the heart-muscle-brain adenine nucleotide translocator isoform 1 (ANT1) was inactivated. ANT1-deficient animals are insulin-hypersensitive, glucose-tolerant, and resistant to high fat diet (HFD)-induced toxicity. In ANT1-deficient skeletal muscle, mitochondrial gene expression is induced in association with the hyperproliferation of mitochondria. The ANT1-deficient muscle mitochondria produce excess reactive oxygen species (ROS) and are partially uncoupled. Hence, the muscle respiration under nonphosphorylating conditions is increased. Muscle transcriptome analysis revealed the induction of mitochondrial biogenesis, down-regulation of diabetes-related genes, and increased expression of the genes encoding the myokines FGF21 and GDF15. However, FGF21 was not elevated in serum, and FGF21 and UCP1 mRNAs were not induced in liver or brown adipose tissue (BAT). Hence, increased oxidation of dietary-reducing equivalents by elevated muscle mitochondrial respiration appears to be the mechanism by which ANT1-deficient mice prevent diabetes, demonstrating that the rate of mitochondrial oxidation of calories is important in the etiology of metabolic disease. mitochondria | skeletal muscle | ANT1 | insulin sensitivity
Nuclear-encoded mutations causing metabolic and degenerative diseases have highly variable expressivity. Patients sharing the homozygous mutation (c.523delC) in the adenine nucleotide translocator 1 gene (SLC25A4, ANT1) develop cardiomyopathy that varies from slowly progressive to fulminant. This variability correlates with the mitochondrial DNA (mtDNA) lineage. To confirm that mtDNA variants can modulate the expressivity of nuclear DNA (nDNA)-encoded diseases, we combined in mice the nDNA Slc25a4 null mutation with a homoplasmic mtDNA ND6 or COI variant. The ND6 variant significantly increased the severity of cardiomyopathy while the COI variant was phenotypically neutral. The adverse Slc25a4 and ND6 combination was associated with impaired mitochondrial complex I activity, increased oxidative damage, decreased l-Opa1, altered mitochondrial morphology, sensitization of the mitochondrial permeability transition pore, augmented somatic mtDNA mutation levels, and shortened lifespan. The strikingly different phenotypic effects of these mild mtDNA variants demonstrate that mtDNA can be an important modulator of autosomal disease.
Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising on the mtDNA haplogroup H7A background, an extremely rare combination. Analysis of transmitochondrial cybrids with the 13708A-H7 mtDNA revealed a lower mitochondrial respiration, increased reactive oxygen species production (mROS), and dysregulation of connective tissue gene expression. The mitochondrial dysfunction was exacerbated by histamine, explaining why all eight surviving children inherited the dysfunctional histidine decarboxylase allele (W327X) from the father. Thus, certain combinations of common mtDNA variants can cause mitochondrial dysfunction, mitochondrial dysfunction can affect extracellular matrix gene expression, and histamine-activated mROS production can augment the severity of mitochondrial dysfunction. Most important, we have identified a previously unreported genetic cause of mitochondrial disorder arising from the incompatibility of common, nonpathogenic mtDNA variants.
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