Evolution of the mitochondrial fusion–fission cycle and its role in aging

Abstract

Mitochondria are organelles of eukaryotic cells that contain their own genetic material and evolved from prokaryotic ancestors some 2 billion years ago. They are the main source of the cell's energy supply and are involved in such important processes as apoptosis, mitochondrial diseases, and aging. During recent years it also became apparent that mitochondria display a complex dynamical behavior of fission and fusion, the function of which is as yet unknown. In this paper we develop a concise theory that explains why fusion and fission have evolved, how these processes are related to the accumulation of mitochondrial mutants during aging, why the mitochondrial DNA has to be located close to the respiration complexes where most radicals are generated, and what selection pressures shaped the slightly different structure of animal and plant mitochondria. We believe that this “organelle control” theory will help in understanding key processes involved in the evolution of the mitochondrial genome and the aging process.

Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?

“…R. Soc. B 369: 20130442 [35]. In order to understand how this system might crumble and permit the accumulation of mutant mtDNA alleles, we first discuss if and under what conditions this system might actually work.…”

“…The proton motive force, generated by the Figure 5. The organelle control theory predicts a 'leaky link' between genotype and phenotype [35]. The tight spatial organization of cristae combined with their microcompartment character leads automatically to such a connection, because the diffusion of mRNAs and proteins synthesized by different nucleoids, N, is impeded by these structures.…”

“…A mathematical model that formalizes the leaky-link model and the possible accumulation of one type of mtDNA mutation, namely partial deletions, takes into account the level of leakiness on the one hand and a possible replicative advantage of smaller-than-wt mtDNA molecules on the other [35]. Computer simulations showed that these counteracting forces have several possible outcomes for genotype selection depending on the boundary conditions.…”

“…Together, this would suggest that nucleoids containing a deleterious mutant mtDNA might, indeed, express a focal OXPHOS phenotype allowing it, in principal, to be selectively degraded via fission/ mitophagy. However, because many mutations are tolerated in disease and accumulate both in disease and with ageing, this indicates that the link between genotype and phenotype is leaky, and intramitochondrial complementation does occur [35]. One might thus pose the question to what extent functional complementation prevents selective degradation of mutant mtDNA molecules and by what means does this complementation take place?…”

What can we infer about the origin of sex in early eukaryotes?

“…It might be instructive to list the other adaptations explained by enhanced endogenous ROS formation. The almost complete bacterial (mitochondrial) genome reduction as a result of migration of genes to the host genome can be understood as an 'escape' from the area flooded by ROS (the mitochondrial genome is attached to its internal membrane [49]) to a more distant area protected by the nuclear membrane. Thus, nuclear membrane formation itself could have come about under pressure of pre-mitochondrial ROS formation (but see also [50]).…”