Mitochondrial DNA mutations activate the mitochondrial apoptotic pathway and cause dilated cardiomyopathy

Abstract

mtDNA mutations therefore are pathogenic, and seem to trigger apoptosis through the mitochondrial pathway.

Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption

“…In addition, mitochondrial DNA mutations have been demonstrated as the underlying factor in several metabolic diseases (43,48) and have their greatest effect in cells that are metabolically active or highly proliferative (39,40,45,49,52). Although the fusion and branching of the villi were previously observed in the small intestine of PolgD257A mice at 10 mo of age (21), they were not prominent features in our 7-mo-old PolgD257A mice.…”

“…Insertions, deletions, and point mutations in the mitochondrial genome have their greatest effect in cells that require high energy production including neurons, hair cells of the inner ears, heart and skeletal myocytes, pancreatic ␤-cells, as well as gut and kidney epithelial cells (39,40,45,49,52). Cell division in a highly regenerative organ like the small intestine also requires high levels of energy production to synthesize lipid, protein, and nucleic acid.…”

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

“…In addition, protein carbonyls, a marker for protein oxidation, are increased in cardiac mitochondria of mtDNA-mutator rodents (36). PolG mice die prematurely from dilated cardiomyopathy, a phenomenon also observed in mice expressing a cardiac-specific proofreadingdeficient PolG (227).…”

“…Treatment of cultured endothelial cells with IGF-1 also preserves ⌬ m , maintaining the mitochondrial retention of cytochrome c and reducing caspase-3 activation upon exposure to H 2 O 2 (76). Furthermore, overexpression of IGF-1 protects mice against high-fat diet feeding-induced increases in ROS generation, thus preventing mitochondrial damage (227). In contrast, low circulating levels of IGF-1 in Ames dwarf mice are associated with increased mitochondrial production of ROS both in the vasculature and the myocardium (29), mimicking the aging phenotype.…”

Mitochondrial DNA polymerase editing mutation, Polg D257A , reduces the diabetic phenotype of Akita male mice by suppressing appetite

“…A large body of data demonstrates links between mitochondrial dysfunction, insulin resistance, and diabetes (1, 2). Deleterious mitochondrial DNA (mtDNA) mutations have their greatest effect in cells that require high energy production, or already have high oxidative stress, including neurons, hair cells of the inner ears, heart and skeletal myocytes, pancreatic beta cells, and gut and kidney epithelial cells (3)(4)(5)(6)(7). Complications of diabetes also involve damage to these metabolically active cell types, leading to a hypothesis that mtDNA mutations contributes to the complications.…”