title: On the relevance of mitochondrial fusions for the accumulation of mitochondrial deletion mutants: a modelling study.
abstract: The molecular mechanisms underlying the aging process are still unclear, but the clonal accumulation of mitochondrial deletion mutants is one of the prime candidates. An important question for the mitochondrial theory of aging is to discover how defective organelles might be selected at the expense of wild-type mitochondria. We propose that mitochondrial fission and fusion events are of critical importance for resolving this apparent contradiction. We show that the occurrence of fusions removes the problems associated with the idea that smaller DNA molecules accumulate because they replicate in a shorter time--the survival of the tiny (SOT) hypothesis. Furthermore, stochastic simulations of mitochondrial replication, mutation and degradation show that two important experimental findings, namely the overall low mosaic pattern of oxidative phosphorylation (OXPHOS) impaired cells in old organisms and the distribution of deletion sizes, can be reproduced and explained by this hypothesis. Finally, we make predictions that can be tested experimentally to further verify our explanation for the age-related accumulation of mitochondrial deletion mutants.
authors.affiliation: Kinetic Modelling Group, Max Planck Institute for Molecular Genetics, Ihnestr. 73, 14195 Berlin, Germany. kowald@molgen.mpg.de
authors.forename: Axel
authors.initials: A
authors.lastname: Kowald
authors.forename: Marina
authors.initials: M
authors.lastname: Jendrach
authors.forename: Sandra
authors.initials: S
authors.lastname: Pohl
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bereiter-Hahn
authors.forename: Peter
authors.initials: P
authors.lastname: Hammerstein
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D003198:Computer Simulation; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D018384:Oxidative Stress
chemical_list: D004272:DNA, Mitochondrial