Mitochondrial DNA (mtDNA) populations within our cells encode vital energetic machinery. MtDNA is housed within mitochondria, cellular compartments lined by two membranes, that lead a very dynamic life. Individual mitochondria can fuse when they meet, and fused mitochondria can fragment to become individual smaller mitochondria, all the while moving throughout the cell. The reasons for this dynamic activity remain unclear (we’ve compared hypotheses about them before here and here, with blog articles here). But what influence do these physical mitochondrial dynamics have on the genetic composition of mtDNA populations?
MtDNA populations can, naturally or as a result of gene therapies, consist of a mixture of different mtDNA types. Typically, different cells will have different proportions of, say, type A and type B. For example, one cell may be 20% type A, another cell may be 40% type A, and a third may be 70% type A. This variability matters because when a certain threshold (often around 60%) is crossed for some mtDNA types, we get devastating diseases.
We previously showed mathematically (blog) and experimentally (blog) that this cell-to-cell variability in mtDNA proportions (often called “heteroplasmy variance” and sometimes referred to via the “mtDNA bottleneck”) is expected to increase linearly over time. However, this analysis pictured mtDNAs as individual molecules, outside of their mitochondrial compartments. When mitochondria fuse to form larger compartments, their mtDNA is more protected: smaller mitochondria (and their internal mtDNA) are subject to greater degradation. More degradation means more replication, and more opportunities for the fraction of a particular type of mtDNA to change per unit time. In a new paper here in Genetics, we show (using a mathematical tour de force by Juvid) that this protection can dramatically influence cell-to-cell mtDNA variability. Specifically, the rate of heteroplasmy variance increase is scaled by the proportion of mitochondria that exist in a fragmented state. (It turns out that it's the proportion of itochondria that are fragmented that's important -- not whether the rate of fission-fusion is fast or slow).
This has knock-on effects for how the cell can best get rid of low-quality mutant mtDNA. In particular, if mitochondria are allowed to fuse based on their quality (“selective fusion”), we show that intermediate rates of fusion are best for removing mutants. Too much fusion, and all mtDNA is protected; too little, and good mtDNA cannot be sorted from bad mtDNA using the mitochondrial network. This mechanism could help explain why we see different levels of mitochondrial fusion in different conditions. More broadly, this link between mitochondrial physics and genetics (which we’ve also speculated about here (blog) and here) suggests one way that selective pressures and tradeoffs could influence mitochondrial dynamics, giving rise to the wide variety of behaviours that remain unexplained. Juvid, Nick, and Iain