Mitochondrial network state scales mtDNA genetic dynamics

Abstract

Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. MtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide-reaching theoretical framework which bridges mitochondrial network and genetic states. We show that, under a range of conditions, the (genetic) rate of increase in heteroplasmy variance and de novo mutation are proportionally modulated by the (physical) fraction of unfused mitochondria, independently of the absolute fission-fusion rate. In the context of selective fusion, we show that intermediate fusion/fission ratios are optimal for the clearance of mtDNA mutants. Our findings imply that modulating network state, mitophagy rate and copy number to slow down heteroplasmy dynamics when mean heteroplasmy is low could have therapeutic advantages for mitochondrial disease and healthy aging.

MtDNA sequence features associated with ‘selfish genomes’ predict tissue-specific segregation and reversion

“…Previous work in plants, where mtDNA recombination produces diverse cellular mtDNA admixtures of potentially different selfishnesses, has shown that multilevel intra- or intercellular selection provides a way of combatting selfish proliferation ( 36 ). The pronounced role for mitochondrial dynamics in imposing intra-cellular quality control ( 30 ), captured by many of these models ( 50–54 , 75 ), suggests that tissue-specific mitochondrial dynamics may play an important role in this multilevel selection and mitigation of selfish proliferation ( 32 , 80 ).…”

Visualizing, quantifying, and manipulating mitochondrial DNA in vivo

“…Mitochondrial network fragmentation is intimately involved in the mechanisms of mitophagy and may also enhance the breakdown of mtDNA (2,12). Altering the levels of the endogenous regulators of mitochondrial network architecture, including Drp1, Opa1 and Mfn1/2 (11), may therefore also impose changes to the mtDNA copy number.…”

“…Mitochondrial DNA (mtDNA) encodes a variety of proteins, peptides, transfer RNAs and ribosomal RNAs that support the functions of mitochondria, and is thereby central to numerous physiological and pathophysiological processes including development, disease and ageing (1). Both the number of mtDNAs in a cell (mtDNA copy number) and the sequences of mtDNAs are important phenotypic determinants (2). Mutations of mtDNA can cause a spectrum of mitochondrial diseases where the clinical expression depends on the specific mutation and the degree of heteroplasmy (the proportion of mutated mtDNA in a single cell) between wild-type and mutant mtDNA (3,4).…”

“…Nucleoids contain complexes of mtDNA with proteins and other factors that comprise the machinery required for regulated transcription (8)(9)(10). The abundance and sequence of mtDNA can affect mitochondrial function while the mitochondrial network, which is regulated by dynamic fission and fusion events (11), can impact upon the turnover and copy number of mtDNA (2,12).…”

Stochastic survival of the densest and mitochondrial DNA clonal expansion in ageing

“…Our work establishes that mitochondrial deletions can expand in muscle fibres without a replicative advantage and, surprisingly, even if mutants are preferentially eliminated from the system. Despite being subject to higher rates of mitophagy -something that finds experimental support [36,37,38,39,40,41] -mutants can come to dominate zones of the fibres. We also predict that the expansion of deletions takes place through a travelling wave of mutants propagating in the muscle fibres.…”