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

Abstract

Mammalian mtDNA encodes for 13 core proteins of oxidative phosphorylation. Mitochondrial DNA mutations and deletions cause severe myopathies and neuromuscular diseases. Thus, the integrity of mtDNA is pivotal for cell survival and health of the organism. We here discuss the possible impact of mitochondrial fusion and fission on mtDNA maintenance as well as positive and negative selection processes. Our focus is centred on the important question of how the quality of mtDNA nucleoids can be assured when selection and mitochondrial quality control works on functional and physiological phenotypes constituted by oxidative phosphorylation proteins. The organelle control theory suggests a link between phenotype and nucleoid genotype. This is discussed in the light of new results presented here showing that mitochondrial transcription factor A/nucleoids are restricted in their intramitochondrial mobility and probably have a limited sphere of influence. Together with recent published work on mitochondrial and mtDNA heteroplasmy dynamics, these data suggest first, that single mitochondria might well be internally heterogeneous and second, that nucleoid genotypes might be linked to local phenotypes (although the link might often be leaky). We discuss how random or site-specific mitochondrial fission can isolate dysfunctional parts and enable their elimination by mitophagy, stressing the importance of fission in the process of mtDNA quality control. The role of fusion is more multifaceted and less understood in this context, but the mixing and equilibration of matrix content might be one of its important functions.

Roles of mitophagy in cellular physiology and development

“…The mechanism of clonal takeover is still being debated (Wallace and Chalkia 2013). One popular hypothesis posits that mitophagy can identify mitochondrial fragments that contain such mutant DNA molecules and Bpurify^the network (Busch et al 2014). This is consistent with the 'late-onset' etiology of these diseases, since autophagy and mitophagy are known to decrease with age in metazoans (Vittorini et al 1999;Cuervo 2008;Lipinski et al 2010;Cui et al 2012).…”

“…Open reading frames encoded by mtDNA encode, as a rule, polytopic integral membrane proteins of the inner mitochondrial membrane, which function in the electron transport chain. One recent discovery has been that, in contrast with mitochondrial matrix protein, these proteins intermix much more slowly within the mitochondrial network (Wilkens et al 2013;Busch et al 2014). In addition, the rate of diffusion of these membrane proteins is similar to that of mitochondrial nucleoids.…”

The road to rack and ruin: selecting deleterious mitochondrial DNA variants

“…Furthermore, gene silencing of ATAD3 induces topological changes in mtDNA, and there appears to be an inverse correlation between nucleoid size and ATAD3 abundance [52]. ATAD3 has its fingers in several pies, as it also physically interacts with mitochondrial ribosomes, based on affinity purification studies [36], and so could play a pivotal role in maintaining a link between mitochondrial translation products and the parent mtDNA molecule [53]. The accessory subunit of mitochondrial DNA polymerase gamma, POLG2, has long been known to have DNA binding properties that are superfluous to its role as a processivity factor [54] and modulating its expression in human cultured cells indicates that it can alter the DNA content of mitochondrial nucleoids [55].…”

What cost mitochondria? The maintenance of functional mitochondrial DNA within and across generations

“…However, to qualify as a unit of selection regular fission is required, followed by selective degradation or delayed fusion of non-functional mitochondria, to counteract the accumulation of fast-replicating mitochondrial genomes [16]. To establish a link between mitochondrial genotype and phenotype for selection to act on, Kowald & Kirkwood [16] suggested a physical attachment between mtDNA genomes and the oxidative phosphorylation complexes they encode [16,18].…”

“…Fusion is thought to maintain homeostasis and to equilibrate nuclear-and mtDNA-encoded mitochondrial proteins [16,17]. An implication of frequent fusion is the possible loss of a direct link between mitochondrial genotype (mtDNA mutations) and phenotype (mitochondrion-specific energy and protongradient deficiencies) because each mitochondrion contains multiple mitochondrial genomes [18]. Thus, while there is competition among individual mtDNA to replicate faster, by reducing genome size, at a higher level the mitochondrion itself is the unit of selection with respect to functionality.…”