disruption of mitochondrial dna replication in drosophila increases mitochondrial fast axonal transport in vivo破坏线粒体dna复制的果蝇增加线粒体快轴突运输体内.pdfVIP

Disruption of Mitochondrial DNA Replication in Drosophila Increases Mitochondrial Fast Axonal Transport In Vivo Rehan M. Baqri1,2,3, Brittany A. Turner1,4, Mary B. Rheuben2,5, Bradley D. Hammond1,2,3, Laurie S. Kaguni3,4, Kyle E. Miller1,2,3* 1 Department of Zoology, Michigan State University, East Lansing, Michigan, United States of America, 2 Neuroscience Program, Michigan State University, East Lansing, Michigan, United States of America, 3 Center for Mitochondrial Science and Medicine, Michigan State University, East Lansing, Michigan, United States of America, 4 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, United States of America, 5 Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, United States of America Abstract Mutations in mitochondrial DNA polymerase (pol c) cause several progressive human diseases including Parkinson’s disease, Alper’s syndrome, and progressive external ophthalmoplegia. At the cellular level, disruption of pol c leads to depletion of mtDNA, disrupts the mitochondrial respiratory chain, and increases susceptibility to oxidative stress. Although recent studies have intensified focus on the role of mtDNA in neuronal diseases, the changes that take place in mitochondrial biogenesis and mitochondrial axonal transport when mtDNA replication is disrupted are unknown. Using high-speed confocal microscopy, electron microscopy and biochemical approaches, we report that mutations in pol c deplete mtDNA levels and lead to an increase in mitochondrial density in Drosophila proximal nerves and muscles, without a noticeable increase in mitochondrial fragmentation. Furthermore, there is a rise in flux of bidirectional mitochondrial axonal transport, albeit with slower kinesin-based anterograde