Disruption of mitochondrial DNA replication in Drosophila increases mitochondrial fast axonal transport in vivo.
Mutations in mitochondrial DNA polymerase (pol gamma) cause several progressive human diseases including Parkinson's disease, Alper's syndrome, and progressive external ophthalmoplegia. At the cellular level, disruption of pol gamma 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 gamma 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 transport. In contrast, flux of synaptic vesicle precursors was modestly decreased in pol gamma-alpha mutants. Our data indicate that disruption of mtDNA replication does not hinder mitochondrial biogenesis, increases mitochondrial axonal transport, and raises the question of whether high levels of circulating mtDNA-deficient mitochondria are beneficial or deleterious in mtDNA diseases.
Baqri
Rehan M
RM
Department of Zoology, Michigan State University, East Lansing, Michigan, USA.
Turner
Brittany A
BA
Rheuben
Mary B
MB
Hammond
Bradley D
BD
Kaguni
Laurie S
LS
Miller
Kyle E
KE
D000818:Animals; D001369:Axons / Q000378:metabolism*; D004247:DNA / Q000737:chemistry; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics*; D004330:Drosophila / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000737:chemistry; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry / Q000379:methods; D016547:Kinesins / Q000737:chemistry; D018613:Microscopy, Confocal / Q000379:methods; D008854:Microscopy, Electron / Q000379:methods; D009154:Mutation; D009930:Organic Chemicals / Q000494:pharmacology
D004272:DNA, Mitochondrial; D009930:Organic Chemicals; C099476:PicoGreen; D049452:Green Fluorescent Proteins; D004247:DNA; D016547:Kinesins