The reductive hotspot hypothesis: an update.
The mitochondrial free radical theory of aging is seriously challenged by the finding that mutant mtDNA never becomes abundant in vivo, a result disputed only in experiments using novel PCR variants whose quantitative accuracy is widely doubted. However, evidence continues to mount that mitochondria are the crucial site of free radical damage in vivo, most notably that mice lacking the nonmitochondrial isoforms of superoxide dismutase are healthy. It is thus important to determine whether a low level of mutant mtDNA could have serious systemic effects. This possibility exists because of the observed mosaic distribution of mutant mtDNA: some cells (or muscle fiber segments) lack any aerobic respiration. Such cells are presumed to satisfy their ATP needs by glycolysis. In vitro, however, NADH recycling by transmembrane pyruvate/lactate exchange does not suffice: cells only survive if they can up-regulate the plasma membrane oxidoreductase (PMOR). The PMOR's physiological electron acceptor is unknown. It was proposed recently (de Grey, A. D. N. J. (1998) J. Anti-Aging Med. 1(1), 53-66) that a prominent in vivo acceptor from these mitochondrially mutant cells may be oxygen, forming extracellular superoxide. The mosaic ("hotspot") distribution of this superoxide would limit its dismutation by extracellular superoxide dismutase; it may thus reduce transition metals leading to oxidation of circulating material, such as LDL. This would raise systemic oxidative stress, greatly amplifying the damage done by the originating mitochondrially mutant cells. This model, now known as the "reductive hotspot hypothesis," has recently gained much indirect experimental support; several direct tests of it are also feasible.
de Grey
A D
AD
Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, United Kingdom. ag24@gen.cam.ac.uk
D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation
D004272:DNA, Mitochondrial; D005609:Free Radicals