Mitochondria and the Ratchet of Doom

How do mitochondria escape Muller's ratchet, the genetic degradation of non-mating cells?

Muller's ratchet is one of the more profound concepts in genetics and evolution. Mutations build up constantly, and are overwhelmingly detrimental. So a clonal population of cells which simply divide and live out their lives will all face degradation, and no matter how intense the selection, will eventually end up mutated in some essential function or set of functions, and die out. This gives rise to an intense desire for organisms to exchange and recombine genetic information. This shuffling process can, while producing a lot of bad hands, also deal out some genetically good hands, purifying away deleterious mutations and combining beneficial ones.

This is the principle behind the meiotic sex of eukaryotes with large genomes, and also the widespread genetic exchange done by bacterial cells, via conjugation and other means. In this way, bacteria can stave off genetic obsolescence, and also pick up useful tricks like antibiotic resistance. But what about our mitochondria? These are also, in origin and essence, bacterial cells with tiny genomes which are critically essential to our well-being. They are maternally inherited, which means that the mitochondria from sperm cells, which could have provided new genetic diversity, are, without the slightest compunction, thrown away. This seriously limits opportunities for genetic exchange and improvement, for a genome that is roughly 16 thousand bases long and codes for 37 genes, many of which are central to our metabolism.

One solution to the problem has been to move genes to the nucleus. Most bacteria have a few thousand genes, so the 37 of the mitochondrial genome are a small remnant, specialized to keep local regulation intact, while the vast majority of needed proteins are encoded in the nucleus and imported through rather ornate mechanisms to take their places in one of the variety of the organelle's locations- inner matrix, inner membrane, inter-membrane space, or outer membrane.

The more intriguing solution, however, has been to perform constant and intensive quality control (with recombination) on mitochondria via a fission and fusion cycle. It turns out that mitochondria are constantly dividing and re-fusing into large networks in our cells. And there are a lot of them- typically thousands in our cells. Mitochondria are also capable of recombination and gene conversion, where parts of one DNA are over-written by copying another DNA molecule. This allows a modicum of gene shuffling among mitochondria in our cells. 

The fusion and fission cycle of mitochondria, where fissioned mitochondria are subject to evaluation for function, and disposal.

Lastly, there is a tight control process that eliminates poorly functioning mitochondria, called mitophagy. Since mitochondria function like little batteries, their charge state is a fundamental measure of health. A nuclear-encoded protein called PINK1 enters the mitochondria, and if the charge state is poor, it remains on the outer membrane to recruit other proteins, including parkin and ubiquitin, which jointly mark the defective mitochondrion for degradation through mitophagy. That means that it is engulfed in an autophagosome and fused with a lysozome, which are the garbage disposal / recycling centers of the cell, filled with acidic conditions and degradative enzymes.

The key point is that during the fission / fusion cycle of mitochondria, which happens over tens of minutes, the fissioned state allows individual or small numbers of genomes to be evaluated, and if defective, disposed of. Meanwhile, the fused state allows genetic recombination and shuffling, to recreate genetic diversity from the ambient mutation rate. Since mitochondria are the centers of metabolism, especially redox reactions, they are especially prone to high rates of mutation. So this surveillance is particularly essential. If all else fails, the whole cell may be disposed of via apoptosis, which is also quite sensitive to the mitochondrial state.

In oocytes, mitochondria appear to go through a particularly stringent period of fission, allowing a high level of quality control at this key point. Additionally, mitochondria then go through exponential growth and energy generation to make the oocyte, at which point those which more quality control discards the oocytes that are not up to snuff.

All this adds up to a pretty thorough method of purifying selection. Admittedly, little or no genetic material comes from outside the clonal maternal genetic lineage, but mutations are probably common enough that beneficial mutations arise occasionally, and one can imagine that there may be additional levels of selection for more successful mitochondria over less successful ones, in addition to the charge-dependent rough cut made by this mitophagy selection.

As the penetrating reader my guess, parkin is related to Parkinson's disease, as one of its causal genes, when defective. Neurons are particularly prone to mitochondrial dysfunction, due to their sprawled-out geography. The nuclear genes needed for mitochondria are made only in the cell body / nucleus, and their products (either as proteins, or sometimes as mRNAs) have to be ferried out to the axonal and dendritic periphery to supply their targets with new materials. Neurons have very active transport systems to do this, but still it is a significant challenge. Second, the local population of mitochondria in outlying processes of neurons is going to be small, making the fission/fusion cycle much less effective and less likely to eliminate defective genes and individual mitochondria, or make up for their absence if they are eliminated, leading to local energetic crises.

Cross-section of a neuronal synapse, with a sprinkling of mitochondria available locally to power local operations.

Papers reviewed here:

• "Mitochondrial fragmentation drives selective removal of deleterious mtDNA in the germline"
• "Avoiding organelle mutational meltdown across eukaryotes with or without a germline bottleneck"
• "Germline selection shapes human mitochondrial DNA diversity"
• "Mitochondrial Fusion, Fission and Autophagy as a Quality Control Axis: The Bioenergetic View"
• "Optimizing mitochondrial maintenance in extended neuronal projections"

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