Mitochondrialdysfunctionresultsindisordersthataffectonein4,000people,anddiseasesassociated withaging,suchasneurodegenerationandcancer.Improperfunctionofamitochondrialqualitycontrol process,mitophagy,aswellasmutationsinmitochondrialDNA(mtDNA)areimplicatedinthese diseases.TheroleofenvironmentalpollutantsandmitophagyintheoriginandtransmissionofmtDNA mutationsispoorlyunderstood.Theobjectiveofthisproposalistoinvestigatevariationinsusceptibility tochemical-inducedmtDNAdamageinthecontextofmitochondrialhomeostaticprocesses,howDNA damagecanleadtomtDNAmutations,andthefunctionalconsequencesofthesemutations.Themodel organismCaenorhabditiseleganshasahighlyconservedmitochondrialgenomeandwellcharacterized mitochondrialbiology,andprovidesanextremelytractablegeneticandtoxicologicalmodelforthis researchproposal.WehypothesizethatC.elegansthataregeneticallydeficientinmitophagywill accumulateandretainhigherlevelsofmtDNAdamagecomparedtowildtypeafterexposuretothe environmentaltoxicantsandknownmutagens,cadmiumandAflatoxinB1.Weproposethatthiswill increasemtDNAmutationfrequencies.Thisworkwillalsoinformtheroleofmitophagyintransmission ofmtDNAmutationsintothenextgeneration.TodetectraremtDNAmutations,wewilladaptawell- establishedandhighly-sensitivesequencingplatform,DuplexSequencing,forC.elegansforthefirst time.Thiswillfulfillasignificantgoalofthetrainingplan,whichistobecomeproficientincomputational biologyandbioinformatics.Wewillalsoinvestigatethepotentialhealtheffectsontheorganism, includingmitochondrialfunction,reproduction,andlifespanasaconsequenceofmtDNAmutations. Overall,thisresearchisimpactfulbecauseitwillprovidebetterunderstandingoftherolethatexposures toenvironmentalpollutantsandgeneticsusceptibilityplayintheorigin,signature,transmission,and effectsofmtDNAmutations.
The effects of chemical toxicants on mitochondrial DNA mutagenesis are not well understood, nor are the processes involved in regulating the transmission of exogenous stress-induced mutations across generations. Therefore, this proposed research project aims to better understand the mechanisms involved in the origin and persistence of mitochondrial DNA mutations after exposure to environmental pollutants. As recent evidence implicates mitochondrial DNA mutations in human diseases such as cancer and neurodegenerative diseases, it is important to better understand the impact that the environment may have on public health.
