OPA1 Mutation and Late‐Onset Cardiomyopathy: Mitochondrial Dysfunction and mtDNA Instability

TLDR

Mitochondrial fusion protein mutations, such as those affecting OPA1, cause inherited neuropathies including Charcot‑Marie‑Tooth disease and dominant optic atrophy. The study aimed to assess cardiac function, mitochondrial performance, and mtDNA stability in a mouse model carrying an OPA1 mutation. Researchers used heterozygous OPA1(+/−) mice to evaluate heart function, mitochondrial morphology, and antioxidant gene expression over time. OPA1(+/−) mice exhibited embryonic lethality when homozygous, but heterozygotes showed reduced mtDNA copy number, lower antioxidant gene expression, age‑related cardiomyopathy with impaired fractional shortening and cardiac output, increased ROS, mitochondrial fragmentation, and concurrent blindness.

Abstract

Mitochondrial fusion protein mutations are a cause of inherited neuropathies such as Charcot-Marie-Tooth disease and dominant optic atrophy. Previously we reported that the fusion protein optic atrophy 1 (OPA1) is decreased in heart failure.We investigated cardiac function, mitochondrial function, and mtDNA stability in a mouse model of the disease with OPA1 mutation. The homozygous mutation is embryonic lethal. Heterozygous OPA(+/-) mice exhibit reduced mtDNA copy number and decreased expression of nuclear antioxidant genes at 3 to 4 months. Although initial cardiac function was normal, at 12 months the OPA1(+/-) mouse hearts had decreased fractional shortening, cardiac output, and myocyte contraction. This coincided with the onset of blindness. In addition to small fragmented mitochondria, aged OPA1(+/-) mice had impaired cardiac mitochondrial function compared with wild-type littermates.OPA1 mutation leads to deficiency in antioxidant transcripts, increased reactive oxygen species, mitochondrial dysfunction, and late-onset cardiomyopathy.