{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:38:15Z","timestamp":1760236695469,"version":"build-2065373602"},"reference-count":68,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T00:00:00Z","timestamp":1639440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM121756"],"award-info":[{"award-number":["R01 GM121756"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["399148","416150"],"award-info":[{"award-number":["399148","416150"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council","doi-asserted-by":"publisher","award":["RGPIN-2019-04302"],"award-info":[{"award-number":["RGPIN-2019-04302"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Huntington\u2019s disease (HD) is one of at least nine polyglutamine diseases caused by a trinucleotide CAG repeat expansion, all of which lead to age-onset neurodegeneration. Mitochondrial dynamics and function are disrupted in HD and other polyglutamine diseases. While multiple studies have found beneficial effects from decreasing mitochondrial fragmentation in HD models by disrupting the mitochondrial fission protein DRP1, disrupting DRP1 can also have detrimental consequences in wild-type animals and HD models. In this work, we examine the effect of decreasing mitochondrial fragmentation in a neuronal C. elegans model of polyglutamine toxicity called Neur-67Q. We find that Neur-67Q worms exhibit mitochondrial fragmentation in GABAergic neurons and decreased mitochondrial function. Disruption of drp-1 eliminates differences in mitochondrial morphology and rescues deficits in both movement and longevity in Neur-67Q worms. In testing twenty-four RNA interference (RNAi) clones that decrease mitochondrial fragmentation, we identified eleven clones\u2014each targeting a different gene\u2014that increase movement and extend lifespan in Neur-67Q worms. Overall, we show that decreasing mitochondrial fragmentation may be an effective approach to treating polyglutamine diseases and we identify multiple novel genetic targets that circumvent the potential negative side effects of disrupting the primary mitochondrial fission gene drp-1.<\/jats:p>","DOI":"10.3390\/ijms222413447","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T22:06:10Z","timestamp":1639519570000},"page":"13447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification of Novel Therapeutic Targets for Polyglutamine Diseases That Target Mitochondrial Fragmentation"],"prefix":"10.3390","volume":"22","author":[{"given":"Annika","family":"Traa","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada"},{"name":"Metabolic Disorders and Complications Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada"},{"name":"Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Machiela","sequence":"additional","affiliation":[{"name":"Laboratory of Aging and Neurodegenerative Disease, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paige D.","family":"Rudich","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada"},{"name":"Metabolic Disorders and Complications Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada"},{"name":"Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja K.","family":"Soo","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada"},{"name":"Metabolic Disorders and Complications Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada"},{"name":"Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan M.","family":"Senchuk","sequence":"additional","affiliation":[{"name":"Laboratory of Aging and Neurodegenerative Disease, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8376-9605","authenticated-orcid":false,"given":"Jeremy M.","family":"Van Raamsdonk","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada"},{"name":"Metabolic Disorders and Complications Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada"},{"name":"Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada"},{"name":"Laboratory of Aging and Neurodegenerative Disease, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA"},{"name":"Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1146\/annurev.neuro.23.1.217","article-title":"Glutamine repeats and neurodegeneration","volume":"23","author":"Zoghbi","year":"2000","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-pathmechdis-012418-012857","article-title":"Polyglutamine repeats in neurodegenerative diseases","volume":"14","author":"Lieberman","year":"2019","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3227","DOI":"10.1093\/hmg\/ddt176","article-title":"Dominant effects of the huntington\u2019s disease htt cag repeat length are captured in gene-expression data sets by a continuous analysis mathematical modeling strategy","volume":"22","author":"Lee","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1212\/WNL.0b013e318249f683","article-title":"Cag repeat expansion in huntington disease determines age at onset in a fully dominant fashion","volume":"78","author":"Lee","year":"2012","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1038\/emboj.2012.65","article-title":"Shaping the role of mitochondria in the pathogenesis of huntington\u2019s disease","volume":"31","author":"Costa","year":"2012","journal-title":"EMBO J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1471-4159.2010.06741.x","article-title":"Nature and cause of mitochondrial dysfunction in Huntington\u2019s disease: Focusing on huntingtin and the striatum","volume":"114","author":"Oliveira","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.mito.2017.03.001","article-title":"Evidence of oxidative stress and mitochondrial dysfunction in spinocerebellar ataxia type 2 (SCA2) patient fibroblasts: Effect of coenzyme Q10 supplementation on these parameters","volume":"34","author":"Cornelius","year":"2017","journal-title":"Mitochondrion"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/hmg\/ddn310","article-title":"Mitochondrial abnormalities in spinal and bulbar muscular atrophy","volume":"18","author":"Ranganathan","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1002\/1531-8249(200007)48:1<72::AID-ANA11>3.0.CO;2-I","article-title":"Abnormal in vivo skeletal muscle energy metabolism in Huntington\u2019s disease and dentatorubropallidoluysian atrophy","volume":"48","author":"Lodi","year":"2000","journal-title":"Ann. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1002\/ana.410410514","article-title":"Oxidative damage and metabolic dysfunction in huntington\u2019s disease: Selective vulnerability of the basal ganglia","volume":"41","author":"Browne","year":"1997","journal-title":"Ann. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1212\/WNL.43.12.2689","article-title":"Evidence for impairment of energy metabolism in vivo in Huntington\u2019s disease using localized 1h nmr spectroscopy","volume":"43","author":"Jenkins","year":"1993","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1093\/hmg\/ddi319","article-title":"HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism","volume":"14","author":"Seong","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nn884","article-title":"Early mitochondrial calcium defects in huntington\u2019s disease are a direct effect of polyglutamines","volume":"5","author":"Panov","year":"2002","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8195","DOI":"10.1128\/MCB.24.18.8195-8209.2004","article-title":"Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro","volume":"24","author":"Trushina","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ferro, A., Carbone, E., Zhang, J., Marzouk, E., Villegas, M., Siegel, A., Nguyen, D., Possidente, T., Hartman, J., and Polley, K. (2017). Short-term succinic acid treatment mitigates cerebellar mitochondrial OXPHOS dysfunction, neurodegeneration and ataxia in a Purkinje-specific spinocerebellar ataxia type 1 (SCA1) mouse model. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188425"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1159\/000339207","article-title":"Patterns of mitochondrial DNA damage in blood and brain tissues of a transgenic mouse model of Machado-Joseph disease","volume":"11","author":"Kazachkova","year":"2013","journal-title":"Neurodegener. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.celrep.2016.08.084","article-title":"Rescue of metabolic alterations in AR113Q skeletal muscle by peripheral androgen receptor gene silencing","volume":"17","author":"Giorgetti","year":"2016","journal-title":"Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s00401-016-1550-4","article-title":"Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet","volume":"132","author":"Rocchi","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1093\/hmg\/ddn404","article-title":"Effects of overexpression of Huntingtin proteins on mitochondrial integrity","volume":"18","author":"Wang","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/nm.2313","article-title":"Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity","volume":"17","author":"Song","year":"2011","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1089\/ars.2012.4928","article-title":"S-nitrosylation of dynamin-related protein 1 mediates mutant huntingtin-induced mitochondrial fragmentation and neuronal injury in Huntington\u2019s disease","volume":"19","author":"Haun","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5371","DOI":"10.1172\/JCI70911","article-title":"Inhibition of mitochondrial fragmentation diminishes Huntington\u2019s disease\u2013associated neurodegeneration","volume":"123","author":"Guo","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Jin, Y.N., Yu, Y.V., Gundemir, S., Jo, C., Cui, M., Tieu, K., and Johnson, G.V. (2013). Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant Huntingtin. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057932"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.yjmcc.2018.12.004","article-title":"Drp1\/fis1-mediated mitochondrial fragmentation leads to lyso-somal dysfunction in cardiac models of Huntington\u2019s disease","volume":"127","author":"Joshi","year":"2019","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1002\/emmm.201000102","article-title":"Mitochondrial fission and cristae disruption increase the response of cell models of Huntington\u2019s disease to apoptotic stimuli","volume":"2","author":"Costa","year":"2010","journal-title":"EMBO Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.14336\/AD.2021.0404","article-title":"Targeting mitochondrial network disorganization is protective in C. elegans models of Huntington\u2019s disease","volume":"12","author":"Machiela","year":"2021","journal-title":"Aging Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"104741","DOI":"10.1016\/j.nbd.2020.104741","article-title":"Mitochondrial fission in Huntington\u2019s disease mouse striatum disrupts ER-mitochondria contacts leading to disturbances in Ca2+ efflux and Reactive Oxygen Species (ROS) homeostasis","volume":"136","author":"Cherubini","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_28","first-page":"1087","article-title":"Increased mitophagy in the skeletal muscle of spinal and bulbar muscular atrophy patients","volume":"26","author":"Borgia","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"368","DOI":"10.3389\/fnmol.2018.00368","article-title":"Mitochondrial morphology, function and homeostasis are impaired by expression of an N-terminal calpain cleavage fragment of ataxin-3","volume":"11","author":"Harmuth","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/j.celrep.2019.01.028","article-title":"Metabolic and organelle morphology defects in mice and human patients define spinocerebellar ataxia type 7 as a mitochondrial disease","volume":"26","author":"Ward","year":"2019","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.bbrc.2018.11.031","article-title":"Inhibition of drp1 hyperactivation reduces neuropathology and behavioral deficits in zq175 knock-in mouse model of huntington\u2019s disease","volume":"507","author":"Zhao","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5305","DOI":"10.1038\/s41467-021-25651-y","article-title":"Small-molecule sup-pression of calpastatin degradation reduces neuropathology in models of huntington\u2019s disease","volume":"12","author":"Hu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.freeradbiomed.2020.11.031","article-title":"Mi-tochondrial sirt3 confers neuroprotection in Huntington\u2019s disease by regulation of oxidative challenges and mitochondrial dynamics","volume":"163","author":"Naia","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/ncb1907","article-title":"Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice","volume":"11","author":"Ishihara","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1056\/NEJMoa064436","article-title":"A lethal defect of mitochondrial and peroxisomal fission","volume":"356","author":"Waterham","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1083\/jcb.200903065","article-title":"The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice","volume":"186","author":"Wakabayashi","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1007\/s00018-019-03024-5","article-title":"Disruption of mitochondrial dynamics affects behaviour and lifespan in Caenorhabditis elegans","volume":"76","author":"Byrne","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1002\/ajmg.a.37721","article-title":"A novel de novo dominant negative mutation in dnm1l impairs mi-tochondrial fission and presents as childhood epileptic encephalopathy","volume":"170","author":"Fahrner","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"8475","DOI":"10.1096\/fj.201903235R","article-title":"Disruption of mitochondrial dynamics increases stress resistance through activation of multiple stress response pathways","volume":"34","author":"Machiela","year":"2020","journal-title":"FASEB J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7597","DOI":"10.1523\/JNEUROSCI.0990-06.2006","article-title":"Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal caenorhabditis elegans model","volume":"26","author":"Brignull","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Firnhaber, C., and Hammarlund, M. (2013). Neuron-specific feeding RNAi in C. elegans and its use in a screen for essential genes required for GABA neuron function. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003921"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/nmeth.1463","article-title":"Enhanced neuronal RNAi in C. elegans using SID-1","volume":"7","author":"Calixto","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1093\/jb\/mvm245","article-title":"An RNAi screen for mitochondrial proteins required to maintain the morphology of the organelle in Caenorhabditis elegans","volume":"143","author":"Ichishita","year":"2008","journal-title":"J. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Huntington\u2019s Study Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes. The huntington\u2019s disease collaborative research group. Cell, 72, 971\u2013983.","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/ng0894-513","article-title":"Identification and characterization of the gene causing type 1 spinocerebellar ataxia","volume":"7","author":"Banfi","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1093\/hmg\/ddg169","article-title":"Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease","volume":"12","author":"Slow","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S0092-8674(00)81369-0","article-title":"Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice","volume":"87","author":"Mangiarini","year":"1996","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"10417","DOI":"10.1073\/pnas.152161099","article-title":"The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans","volume":"99","author":"Morley","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1093\/hmg\/ddl017","article-title":"Suppression of polyglutamine-induced toxicity in cell and animal models of huntington\u2019s disease by ubiquilin","volume":"15","author":"Wang","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"13318","DOI":"10.1073\/pnas.231476398","article-title":"Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death","volume":"98","author":"Parker","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6403","DOI":"10.1073\/pnas.0307697101","article-title":"From the cover: Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation","volume":"101","author":"Nollen","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Lejeune, F.X., Mesrob, L., Parmentier, F., Bicep, C., Vazquez-Manrique, R.P., Parker, J.A., Vert, J.P., Tourette, C., and Neri, C. (2012). Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons. BMC Genom., 13.","DOI":"10.1186\/1471-2164-13-91"},{"key":"ref_53","first-page":"20151028","article-title":"Variation in the link between oxygen consumption and ATP production, and its relevance for animal performance","volume":"282","author":"Salin","year":"2015","journal-title":"Proc. Biol. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.bbabio.2010.01.004","article-title":"Mitochondrial energy metabolism and ageing","volume":"1797","author":"Bratic","year":"2010","journal-title":"Biochim. Biophys. Acta BBA Bioenerg."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.mad.2009.05.001","article-title":"C. elegans longevity pathways converge to decrease mitochondrial membrane potential","volume":"130","author":"Lemire","year":"2009","journal-title":"Mech. Ageing Dev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"16441","DOI":"10.1038\/s41598-017-16637-2","article-title":"Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in parkinson\u2019s disease models","volume":"7","author":"Cooper","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"108477","DOI":"10.1016\/j.abb.2020.108477","article-title":"Inhibition, crystal structures, and in-solution oligomeric structure of aldehyde dehydrogenase 9A1","volume":"691","author":"Wyatt","year":"2020","journal-title":"Biochem. Biophys."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1002\/j.1460-2075.1993.tb05806.x","article-title":"The expression of two P-glycoprotein (pgp) genes in transgenic Caenorhabditis elegans is confined to intestinal cells","volume":"12","author":"Lincke","year":"1993","journal-title":"EMBO J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0092-8674(00)80958-7","article-title":"Molecular mechanisms of bacterial virulence elucidated using a Pseudomonas aeruginosa\u2013Caenorhabditis elegans pathogenesis model","volume":"96","author":"Tan","year":"1999","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1002\/j.1460-2075.1995.tb07178.x","article-title":"A P-glycoprotein protects Caenorhabditis elegans against natural toxins","volume":"14","author":"Broeks","year":"1995","journal-title":"EMBO J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"777","DOI":"10.18632\/aging.100939","article-title":"Aging causes decreased resistance to multiple stresses and a failure to activate specific stress response pathways","volume":"8","author":"Dues","year":"2016","journal-title":"Aging"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1534\/g3.117.040824","article-title":"Reliable CRISPR\/Cas9 Genome Engineering in Caenorhabditis elegans Using a Single Efficient sgRNA and an Easily Recognizable Phenotype","volume":"7","author":"Lecroisey","year":"2017","journal-title":"G3 Genes Genomes Genet."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Wu, Z., Senchuk, M.M., Dues, D.J., Johnson, B.K., Cooper, J.F., Lew, L., Machiela, E., Schaar, C.E., Dejonge, H., and Blackwell, T.K. (2018). Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways. BMC Biol., 16.","DOI":"10.1186\/s12915-018-0615-3"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"15022","DOI":"10.1038\/npjparkd.2015.22","article-title":"Delaying aging is neuroprotective in parkinson\u2019s disease: A genetic analysis in C. elegans models","volume":"1","author":"Cooper","year":"2015","journal-title":"NPJ Parkinson\u2019s Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.mad.2011.08.006","article-title":"FUdR causes a twofold increase in the lifespan of the mitochondrial mutant gas-1","volume":"132","author":"Hekimi","year":"2011","journal-title":"Mech. Ageing Dev."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Schaar, C.E., Dues, D.J., Spielbauer, K.K., Machiela, E., Cooper, J.F., Senchuk, M., Hekimi, S., and Van Raamsdonk, J.M. (2015). Mitochondrial and cytoplasmic ros have opposing effects on lifespan. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1004972"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2016.08.008","article-title":"Oxidative stress is increased in C. elegans models of Huntington\u2019s disease but does not contribute to polyglutamine toxicity phenotypes","volume":"96","author":"Machiela","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Senchuk, M.M., Dues, D.J., Schaar, C.E., Johnson, B.K., Madaj, Z.B., Bowman, M.J., Winn, M.E., and Van Raamsdonk, J.M. (2018). Activation of daf-16\/foxo by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in Caenorhabditis elegans. 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