The reductive hotspot hypothesis of mammalian aging: membrane metabolism magnifies mutant mitochondrial mischief.
A severe challenge to the idea that mitochondrial DNA mutations play a major role in the aging process in mammals is that clear loss-of-function mutations accumulate only to very low levels (under 1% of total) in almost any tissue, even by very old age. Their accumulation is punctate: some cells become nearly devoid of wild-type mitochondrial DNA and exhibit no activity for the partly mitochondrially encoded enzyme cytochrome c oxidase. Such cells accumulate in number with aging, suggesting that they survive indefinitely, which is itself paradoxical. The reductive hotspot hypothesis suggests that these cells adjust their metabolism to use plasma membrane electron transport as a substitute for the mitochondrial electron transport chain in the reoxidation of reduced dinucleotides, and that, like mitochondrial electron transport, this process is imperfect and generates superoxide as a side-effect. This superoxide, generated on the outside of the cell, can potentially initiate classical free radical chemistry including lipid peroxidation chain reactions in circulating material such as lipoproteins. These, in turn, can be toxic to mitochondrially nonmutant cells that import them to satisfy their cholesterol requirements. Thus, the relatively few cells that have lost oxidative phosphorylation capacity may be toxic to the rest of the body. In this minireview, recent results relevant to this hypothesis are surveyed and approaches to intervening in the proposed process are discussed.
de Grey
Aubrey D N J
AD
Department of Genetics, University of Cambridge, UK. ag24@gen.cam.ac.uk
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D010085:Oxidative Phosphorylation; D013481:Superoxides / Q000378:metabolism*
D004272:DNA, Mitochondrial; D013481:Superoxides