OPA1 mutant in a mouse model leads to cardiac dysfunctions via depressing the mitochondrial respiration

We previously reported that expression of OPA1, a mitochondrial fusion protein, was decreased in both human and rat failing hearts. Inherited neuropathies are associated with mutation of fission/fusion proteins. We hypothesized a mutation of OPA1 in mouse would lead to cardiac dysfunction via impaired mitochondrial function. The homozygote mutation B6;C3‐Opa1 mouse is embryonic lethal. The heterozygote has a 50% reduction in OPA1 transcript and protein in the heart and is associated with cardiac dysfunction in addition to visual defects. The OPA1+/− mouse hearts showed atrophy at 12 months and weighed 116.3 ± 14.8 mg, while wild type (WT) hearts were 236.5 ± 24.4 mg (P < 0.05). OPA1+/− hearts had decreased fractional shortening by echo compared with WT. Hemodynamic data showed a narrowed pressure‐volume loop as well as decreased cardiac output. Electron microscopy in the OPA1+/− hearts demonstrated small fragmented mitochondria compared to WT, indicating the loss of mitochondrial fusion in OPA1+/− hearts. Mitochondrial complex II activity decreased significantly in OPA1+/− mouse hearts, but, interestingly, complex I and III were unchanged compared to WT. In conclusion, OPA1 mutation leads to depressed mitochondrial fusion and decreased complex II activity. These abnormalities are associated with depressed cardiac function and atrophy. Supported by NIH HL077281, HL079071, and a Merit Award from VA.