Dynamin-related protein 1 heterozygote knockout mice do not have synaptic and mitochondrial deficiencies

Abstract

The objective of this study was to elucidate the effect of partial reduction of the mitochondrial fission protein, dynamin-related protein 1 (Drp1) on mitochondrial activity and synaptic viability. Recent knockout studies of Drp1 revealed that homozygote Drp1 knockout mice are embryonic lethal due to reduced mitochondrial fission, and that this reduced fission leads to developmental defects in the brain. In contrast, heterozygote Drp1 knockout mice appear to be normal in terms of lifespan, fertility, and viability, and phenotypically these animals are not different from wild-type mice. However, the effects of partial Drp1 reduction on mitochondrial function and synaptic activity are not well understood. In the present study, we sought to characterize synaptic, dendritic and mitochondrial proteins, and mitochondrial function and GTPase enzymatic activity, in Drp1 heterozygote knockout mice. Interestingly, we found no significant changes in synaptic, dendritic, and mitochondrial proteins in the Drp1 heterozygote knockout mice compared to the wild-type mice. Further, mitochondrial function and GTPase enzymatic activity appeared to be normal. However, H2O2 and lipid peroxidation levels were significantly reduced in the Drp1 heterozygote knockout mice compared to the wild-type mice. These findings suggest that partial Drp1 reduction does not affect mitochondrial and synaptic viability and may have therapeutic use in treating patients with Alzheimer’s disease and Huntington’s disease.

Multiple faces of dynamin-related protein 1 and its role in Alzheimer's disease pathogenesis

“…More recently, the Reddy laboratory has reported abnormal mitochondrial dynamics (increased fission and decreased fusion), Aβ interaction with Drp1, increased mitochondrial fragmentation and impaired axonal transport and synaptic degeneration [38, 39, 73, 139, 140]. These abnormalities increased with disease progression.…”

“…Recently, Reddy laboratory [38,39] studied effects of partial Drp1 reduction on mitochondrial function and synaptic activity. They sought to characterize synaptic, dendritic and mitochondrial proteins, and mitochondrial function and GTPase enzymatic activity, in Drp1 heterozygote knockout mice.…”

“…However, H 2 O 2 and lipid peroxidation levels were significantly reduced in the Drp1 heterozygote knockout mice compared to the wild-type mice. They speculated these findings suggest that partial Drp1 reduction does not affect mitochondrial and synaptic viability [38, 39]. …”

In vivo functions of Drp1: Lessons learned from yeast genetics and mouse knockouts

“…The architecture of the heart appears normal, although isolated cardiomyocytes show decreased beating rate, suggesting that functional defects in the heart may also contribute to embryonic death. Heterozygous Drp1KO mice have levels of Drp1 that are decreased by 20%–30%, but these animals are normal in birth, growth, and mating [91, 93]. Mitochondrial morphology also appears normal in heterozygous Drp1KO mice, suggesting that mitochondrial division is not severely affected [93].…”

“…Heterozygous Drp1KO mice have levels of Drp1 that are decreased by 20%–30%, but these animals are normal in birth, growth, and mating [91, 93]. Mitochondrial morphology also appears normal in heterozygous Drp1KO mice, suggesting that mitochondrial division is not severely affected [93]. Partial decreases in Drp1 levels are, therefore, tolerated in mice.…”