Wednesday, 27 February 2019

How mitochondria can vary, and consequences for human health


Mitochondria are components of the cell which are involved in generating “energy currency” molecules called ATP across much of complex life. Since many mitochondria exist within single cells (often hundreds or thousands), it is possible for the characteristics of individual mitochondria to vary within cells, and within tissues. This variation of mitochondrial characteristics can affect biological function and human health.

Since mitochondria possess their own, small, circular, DNA molecules (mtDNA), we can split mitochondrial characteristics into two categories: genetic and non-genetic. In our review, we discuss a number of aspects in which mitochondria vary, from both genetic and non-genetic perspectives. 



In terms of mitochondrial genetics, the amount of mtDNA per cell is variable. When a cell divides, its daughters receive a share of its parents mtDNA, but the split isn’t precisely 50/50, so cell division can cause variability in the number of mtDNAs per cell. As mtDNAs are replicated and degraded over time, errors in the copying process may give rise to mtDNA mutations, which may spread throughout a cell. Factors such as: the total amount, the rate of degradation/replication, the mean fraction of mutants, and the extent of fragmentation in the mitochondrial network, can all influence how variable the fraction of mutated mtDNAs becomes through time (see here for a preview of some upcoming work on this topic). The total amount, and mutated fraction of mtDNAs, are implicated in diseases such as neurodegeneration, as well as the ageing process.

Apart from genetic variations, there are many non-genetic features of mitochondria which also vary within and between cells. Changes in mtDNA sequence can change the amino-acid sequence of the proteins encoded by mtDNA, causing structural changes in the molecular machines which generate ATP. The shape of the membranes of mitochondria are also highly variable, and respond to mitochondrial activity through quantities such as pH, where mitochondrial activity itself may depend on mtDNA sequence. The previous two examples (mitochondrial protein and membrane structure) demonstrate how the genetic state of mitochondria may influence their non-genetic characteristics. Mitochondrial non-genetic characteristics may also influence the genetic state: for instance, mitochondrial membrane potential can influence the probability of a mitochondria being degraded, along with its mtDNA.

The inter-dependence of genetic and non-genetic characteristics demonstrate the complex feedback loops linking these two aspects of mitochondrial physiology. We suggest here that, since changes in mitochondrial genetics occur more slowly than most physical aspects of mitochondrial physiology, understanding mitochondrial genetics may be especially important in explaining phenomena such as ageing, which appears to be closely related to mitochondrial heterogeneity. You can freely access our work, which has recently been published in Frontiers in Genetics, as “Mitochondrial Heterogeneity” https://www.frontiersin.org/articles/10.3389/fgene.2018.00718/full Juvid, Iain and Nick.
 

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