title: TAp73 depletion accelerates aging through metabolic dysregulation.
abstract: Aging is associated with impaired scavenging of reactive oxygen species (ROS). Here, we show that TAp73, a p53 family member, protects against aging by regulating mitochondrial activity and preventing ROS accumulation. TAp73-null mice show more pronounced aging with increased oxidative damage and senescence. TAp73 deletion reduces cellular ATP levels, oxygen consumption, and mitochondrial complex IV activity, with increased ROS production and oxidative stress sensitivity. We show that the mitochondrial complex IV subunit cytochrome C oxidase subunit 4 (Cox4i1) is a direct TAp73 target and that Cox4i1 knockdown phenocopies the cellular senescence of TAp73-null cells. Results indicate that TAp73 affects mitochondrial respiration and ROS homeostasis, thus regulating aging.
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester, United Kingdom.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rufini
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Niklison-Chirou
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Richard
authors.initials: R
authors.lastname: Tomasini
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Harris
authors.forename: Arianna
authors.initials: A
authors.lastname: Marino
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
authors.forename: David
authors.initials: D
authors.lastname: Dinsdale
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.forename: Tak Wah
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003576:Electron Transport Complex IV / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D010101:Oxygen Consumption; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D029961:Zebrafish Proteins; C477072:tp73 protein, zebrafish; D003576:Electron Transport Complex IV