title: Role of mitochondria in oxidative stress and aging.
abstract: The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), considered as the pathogenic agent of many diseases and of aging. We have investigated the role of Complex I in superoxide radical production and found by combined use of specific inhibitors of Complex I that the one-electron donor in the Complex to oxygen is a redox center located prior to the sites where three different types of coenzyme Q (CoQ) competitors bind, to be identified with an Fe-S cluster, most probably N2, or possibly an ubisemiquinone intermediate insensitive to all the above inhibitors. Short-chain coenzyme Q analogues enhance superoxide formation, presumably by mediating electron transfer from N2 to oxygen. The clinically used CoQ analogue idebenone is particularly effective, raising doubts about its safety as a drug. The mitochondrial theory of aging considers somatic mutations of mitochondrial DNA induced by ROS as the primary cause of energy decline; in rat liver mitochondria, Complex I appears to be most affected by aging and to become strongly rate limiting for electron transfer. Mitochondrial energetics is also deranged in human platelets upon aging, as demonstrated by the decreased Pasteur effect (enhancement of lactate production by respiratory inhibitors). Cells counteract oxidative stress by antioxidants: CoQ is the only lipophilic antioxidant to be biosynthesized. Exogenous CoQ, however, protects cells from oxidative stress by conversion into its reduced antioxidant form by cellular reductases. The plasma membrane oxidoreductase and DT-diaphorase are two such systems: likewise, they are overexpressed under oxidative stress conditions.
authors.affiliation: Dipartimento di Biochimica G. Moruzzi, Università di Bologna, Via Irnerio 48, 40126 Bologna, Italy. lenaz@biocfarm.unibo.it
authors.forename: Giorgio
authors.initials: G
authors.lastname: Lenaz
authors.forename: Carla
authors.initials: C
authors.lastname: Bovina
authors.forename: Marilena
authors.initials: M
authors.lastname: D'Aurelio
authors.forename: Romana
authors.initials: R
authors.lastname: Fato
authors.forename: Gabriella
authors.initials: G
authors.lastname: Formiggini
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Genova
authors.forename: Giovanni
authors.initials: G
authors.lastname: Giuliano
authors.forename: Milena
authors.initials: M
authors.lastname: Merlo Pich
authors.forename: Ugo
authors.initials: U
authors.lastname: Paolucci
authors.forename: Giovanna
authors.initials: G
authors.lastname: Parenti Castelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Ventura
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D019069:Cell Respiration / Q000502:physiology; D004579:Electron Transport; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014451:Ubiquinone / Q000378:metabolism
chemical_list: D013481:Superoxides; D014451:Ubiquinone; D010088:Oxidoreductases