Mitochondrial dynamics and autophagy aid in removal of persistent mitochondrial DNA damage in Caenorhabditis elegans.
Mitochondria lack the ability to repair certain helix-distorting lesions that are induced at high levels in mitochondrial DNA (mtDNA) by important environmental genotoxins and endogenous metabolites. These lesions are irreparable and persistent in the short term, but their long-term fate is unknown. We report that removal of such mtDNA damage is detectable by 48 h in Caenorhabditis elegans, and requires mitochondrial fusion, fission and autophagy, providing genetic evidence for a novel mtDNA damage removal pathway. Furthermore, mutations in genes involved in these processes as well as pharmacological inhibition of autophagy exacerbated mtDNA damage-mediated larval arrest, illustrating the in vivo relevance of removal of persistent mtDNA damage. Mutations in genes in these pathways exist in the human population, demonstrating the potential for important gene-environment interactions affecting mitochondrial health after genotoxin exposure.
Duke University, Nicholas School of Environment, Integrated Toxicology and Environmental Health Program, LSRC, PO Box 90328, Durham, NC 27708, USA.
Amanda S
AS
Bess
Tracey L
TL
Crocker
Ian T
IT
Ryde
Joel N
JN
Meyer
D000818:Animals; D001343:Autophagy; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000528:radiation effects; D004249:DNA Damage; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000378:metabolism* / Q000528:radiation effects; D007814:Larva / Q000235:genetics / Q000528:radiation effects; D008928:Mitochondria / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D014466:Ultraviolet Rays / Q000009:adverse effects
D004272:DNA, Mitochondrial