Mitochondria age within a post mitotic (non-dividing) cell as a result of a cessation in their own renewal by replication and, when aged, are more likely to trigger apoptosis (cell death). Some mitochondria ( for example in birds and bats) seem better ‘made’ than others and as a result the animals age more slowly than do other of similar size. Mitochondria the evidence shouts over and over are the arbitrators of apoptosis. The question is not how is this is well known, but why?
Multicellular creatures possess mitochondria for the simple reason that they simply could not produce the amounts of energy needed for movement, nervous conduction and digestion without them. To liberate the energy to do this kind of work mitochondria combine oxygen with simple carbon compounds in a process called oxidative phosphorylation … and can do so at an impressive rate, enough to power huge brains and athletic bodies. But the price to pay is mortality. Maybe this is a little ironic given that mitochondria and their hosts are descendants of immortal creatures. Truly a Faustian pact.
This article however is about cells that don’t really need such a high-rolling lifestyle, cells that live near anoxic lives within the multicellular furnaces of the mammal. How do they get on with their suicidal mitochondrial guests when really they don’t need them?
The answer to this question is both intriguing and consistent with what we know about mitochondria. It’s accepted that the multicellular life requires mitochondria to provide the energy to maintain the organism, but it is not the case that mitochondrial energy is needed to power cell division. This means that in anoxic or near anoxic environments, within the organism, growth and reproduction carries on without the need for the mitochondria’s power pack. Below are some interesting examples.
Chondrocytes are the cells that secrete the substrate for the cartilage matrix and, as is well known, the aging mammal suffers badly from deteriorating joint cartilage. Research shows that the chondrocytes are in quite anoxic environments and happily go about their work using only the energy from glycolysis, however the few mitochondria that they possess still apparently want their say over cell death. The aging and deteriorating chondrocyte has the signature profile of leaking and depolarising mitochondria known to be responsible for cell death in other tissues 1. All the pain and none of the gain for the cohabiting mitochondria is the phrase that comes to mind.
Next up are the white adipocytes better know as fat cells. These have very few mitochondria and in the centre of fat masses we see anoxic conditions and once again a reliance on glycolysis. Aging and senescent adipocytes are very much in the frame for the onset of insulin resistance with age and the onset of Type 2 diabetes. This is associated with increased oxidative stress2 ( a mitochondrial signature) but I can find no direct work on the role that mitochondria play ... but I have my suspicions!
Cancer cells are notoriously biased towards the anoxic life as made famous by the Warburg effect3, and indeed it was thought that their predisposition towards anaerobic glycolysis and away from mitochondrial oxidative phosphorylation means that cancer cells do not need mitochondria.
It turns out that the picture is quite complicated. Indeed many cancer cells do ‘eat up’ excess mitochondria (mitophagy) and also inhibit their production of ATP but they also seem to ‘benefit’ from increased ROS (reactive oxygen species) production in that it has a mutagenic and hence potentially transforming ( cancer producing) plus side … but also they seem to be able to do this whilst inhibiting the mitochondria’s apotoptic abilities4. This is truly intriguing and can be put this way: Cells which atavistically ‘revert’ to an immortal anaerobic state actually leverage the ROS mutagenic potential of their malfunctioning mitochondrial symbionts while at the same time disabling their ability to destroy their host … amazing.
Finally we have eukaryote cells which have gone the whole hog and ditched mitochondria ... genes and all. Monocercomonoidesis5 a unicellular flagellate living in the near-anoxic gut biome which is the environment bounded by the gut in which our gut flora live. Monocercomonoidesis is recently famous because it has been shown to have: no mitochondria; no genes for mitochondria in its nucleus and has borrowed a bacterium’s iron-sulfur complex to do a bit of essential chemistry that the mitochondria were doing.
It uses its ancestral glycolytic pathway and is doing just fine even though it appears to re-write the definition of an eukaryotic cell which is supposed to have mitochondria even if few and virtually vestigial. Basically, it has ditched a couple of billion years of evolution. But why?
This whirlwind tour of the near anoxic world of the eukaryote cell has posed a few conundrums.
Firstly, one paradigm remains intact and that is that mitochondria-deplete cells are in effect either unicellular ( eg Monocercomonoides or chondrocytes) or are in poorly vasculated undifferentiated tissues masses ( tumours or adipose tissue).
We also can see that mitochondria are ‘expensive’ and are not conserved or are poorly conserved in cells which don’t need them. It also looks like they are in whatever context regarded as lethal. The question is begged as to whether ditching mitochondria in some settings is a good idea or whether they perform a vital housekeeping function destroying post-mitotic cells that are past their ‘cell-by’ date, pun intended.
Whatever, the picture I am seeing more clearly than ever is one of an intracellular ecosystem, a miniature eurozone of complex interdependencies. Monocercomonoides has lost one of its prominent members, though we don’t know quite when or whether it has done it alone. Evolution can go ‘backwards’ as well as ‘forwards’
No comments:
Post a Comment