title: 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.
authors.affiliation: Division of Mitochondrial Dynamics, School of Biology and Chemistry, University of Osnabrück, 49069 Osnabrück, Germany.
authors.forename: Karin B
authors.initials: KB
authors.lastname: Busch
authors.affiliation: Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
authors.forename: Axel
authors.initials: A
authors.lastname: Kowald
authors.affiliation: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Medical Centre, Geert Grooteplein 10, PO Box 9101, 6500 HB Nijmegen, The Netherlands FinMIT Centre of Excellence, Institute of Biomedical Technology and Tampere University Hospital, Pirkanmaa Hospital District, 33014 Tampere, Finland hans.spelbrink@radboudumc.nl.
authors.forename: Johannes N
authors.initials: JN
authors.lastname: Spelbrink
mesh_terms: D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D063306:Mitophagy / Q000235:genetics / Q000502:physiology; D012641:Selection, Genetic
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins
keywords: OXPHOS; TFAM; mitochondrial dynamics; mitophagy; mtDNA; nucleoids