Mitochondrial function and lifespan of mice with controlled ubiquinone biosynthesis.
Ubiquinone (UQ) is implicated in mitochondrial electron transport, superoxide generation and as a membrane antioxidant. Here we present a mouse model in which UQ biosynthesis can be interrupted and partially restored at will. Global loss of UQ leads to gradual loss of mitochondrial function, gradual development of disease phenotypes and shortened lifespan. However, we find that UQ does not act as antioxidant in vivo and that its requirement for electron transport is much lower than anticipated, even in vital mitochondria-rich organs. In fact, severely depressed mitochondrial function due to UQ depletion in the heart does not acutely impair organ function. In addition, we demonstrate that severe disease phenotypes and shortened lifespan are reversible upon partial restoration of UQ levels and mitochondrial function. This observation strongly suggests that the irreversible degenerative phenotypes that characterize ageing are not secondarily caused by the gradual mitochondrial dysfunction that is observed in aged animals.
Department of Biology, McGill University, Montreal, Quebec, Canada H3A 1B1.
Ying
Y
Wang
Department of Biology, McGill University, Montreal, Quebec, Canada H3A 1B1.
Daniella
D
Oxer
Department of Biology, McGill University, Montreal, Quebec, Canada H3A 1B1.
Siegfried
S
Hekimi
D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism; D020868:Gene Silencing; D015151:Immunoblotting; D019426:Integrases; D008136:Longevity / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics; D006899:Mixed Function Oxygenases; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014451:Ubiquinone / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism*
D016227:Benzoquinones; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C004532:quinone; D006899:Mixed Function Oxygenases; C434481:Coq7 protein, mouse; C045073:Cre recombinase; D019426:Integrases