The D210V mutation of Mfn2 in neurons induces different pathologies in severity depends on its expression timing
Kaori Ishikawa1,2, Satoshi Yamamoto3, Satoko Hattori4, Naoya Nishimura3, Takayuki Mito1, Hirokazu Matsumoto3, Tsuyoshi Miyakawa4, Kazuto Nakada1,2,5*
1Faculty of Life and Environmental Sciences, University of Tsukuba; 2 Graduate School of Life and Environmental Sciences, University of Tsukuba; 3Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd; 4Division of System Medical Science, Institute for Comprehensive Medical Science, Fujita Health University; 5Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba
Neurons are known for their plasticity especially during growth phase of individuals, because they construct complex networks from embryonic stage to adult phase. Controlling mitochondrial dynamics is important to maintain normal neuronal functions because it is necessary to distribute mitochondria as energy plants not only around cell bodies but also dendrites and axons. However, the relation between mitochondrial dynamics and neuronal plasticity or maintain of neuronal function was unclear. To investigate the impact of abnormalities of mitochondrial dynamics growth stage dependently, we established a mouse strain expressing mutant of mitochondrial fusion factor Mfn2 neuron specifically and inducibly. The group expressing mutant Mfn2 from birth showed atrophy of cerebral cortex shortly, and about half of mice died within 8-10 weeks. On the other hand, the group expressing the mutant after maturation showed no severe phenotype until 150 days after the start of expression. However, after that, reduced weight gain and mitochondrial dysfunction were recognized, and remarkable abnormalities of behavior and learning were observed after day 300. These observations mean that abnormal mitochondrial dynamics in neurons has great impact on survival in juvenile phase, and has severe influence on neuronal functions even after adulthood. These results indicate that homeostasis of mitochondrial dynamics is important throughout life for the normal functions of neuronal cells.