How Age-Damaged Mitochondria Cause Your Cells To Age-Damage You

Methuselah Foundation
Free radicals, and reactive oxygen species (ROS) in particular, play an important part in aging. These are (usually small) molecules lacking an electron needed for stability; they will steal an electron from the first thing they bump into. Like pulling a cog out from clockwork, stealing an electron from a protein or enzyme is usually not good for the finely-tuned biochemical machinery of our cells. The free radical might be rendered safe in the process, but it has left some form of chaos and damage in its wake.

Free radicals are sufficiently dangerous to biochemical machinery that some of our body’s defenders use bursts of free radicals as a kill mechanism.

Scientists generally concur that accumulated damage throughout the body due to free radicals is one important root cause of age-related degeneration – but the devil is in the details. The vast, overwhelming majority of those free radicals are generated by your own metabolism as an unavoidable byproduct. The rate of free radical generation increases greatly with age as the basic mechanisms of your of metabolism are themselves damaged by the free radicals they created. This is not a one-step process, however. I’ll try to walk through it at a high level, cribbing from the mitochondrial free radical theory of aging proposed by Aubrey de Grey and working its way into general acceptance.

Within each of your cells are many mitochondria, tiny biochemical power plants that convert chemicals from food to ATP, the basic fuel molecule used by your cells to provide energy for life.

Mitochondria were once a separate organism that came to live in symbiosis with ancestral cells. As such, they brought their own DNA to the party; some of it still remains within our mitochondria, separate from the DNA we carry in chromosomes in the cell nucleus.
Mitochondria have a couple of ways of generating ATP. The more efficient of these methods – oxidative phosphorylation (OXPHOS) – generates some amount of free radicals as a natural byproduct, and requires the proteins coded in the mitochondrial DNA to function. It is the predominant way by which healthy cells generate their power.

A great deal of work is needed to make this happen, even with today’s biotechnology. But if you don’t get started, you’ll certainly never finish! Generous donations to the Methuselah Foundation help to fund the first steps in this direction.

Free radicals created through OXPHOS within a mitochondrion are most likely to damage that mitochondrion; they’re very reactive, so they won’t get far before sabotaging something. The components that really matter are (a) a membrane that helps organize the movement of various chemicals in the process of generating ATP, and (b) the mitochondrial DNA.
Sufficient free radical damage to mitochondrial DNA shuts down OXPHOS within that mitochondrion, as the necessary proteins can no longer be produced. The mitochondrion switches over to using a less efficient method of producing power, one that doesn’t produce free radicals, but has to run at a much higher rate to produce the same level of ATP.

Mitochondria, like most cellular components, are recycled on a regular basis. Components called lysosomes are directed around the cell in response to various signals, engulfing and breaking down damaged or worn components. After the herd has been culled, surviving mitochondria within a cell divide and replicate, much like bacteria, to make up the numbers.
The signal to break down a mitochondrion is triggered by sufficient damage to its membrane: a sign that it’s old, leaky, inefficient and needs to be replaced with a shiny new power plant.

BUT: if a mitochondrion has had its DNA damaged to the point of stopping OXPHOS, it will no longer be producing free radicals that can damage its membrane. So it will never get broken down by a lysosome. When the time comes to divide and replicate, it will replicate its damaged DNA into new mitochondria. None of those new mitochondria will be producing free radicals via OXPHOS, and so will not be recycled either.

One DNA-damaged, non-OXPHOS mitochondrion will eventually take over the entire mitochondrial population of a cell in this way. At that point, the trouble really gets started.
By the time you hit late life, perhaps 1% of your cells are in this state of being taken over by non-OXPHOS mitochondria. As for any neighborhood or city, it only takes a small proportion of dangerous criminals to make life really unpleasant for the rest of us.

Non-OXPHOS mitochondria have the unfortunate effect of depleting a needed molecule used in many cellular processes, NAD+. This is a carrier molecule in the OXPHOS process, given an electron (and turned into NADH in the process) to port between point A and point B within the mitochondria. Once the electron is delivered, the NADH becomes NAD+ again. But without a working OXPHOS process to return NAD+ into circulation, the cell would quickly build up a deadly excess of NADH, run out of NAD+ and die.

Fortunately for the cell, and unfortunately for us, there is another way to recycle NADH into NAD+. Since NADH is just NAD+ with an electron stuck to it, all the cell has to do is export those unwanted electrons.

In a form of chemical waste dumping, this is just what the cell does. Structures on the cell membrane known as the plasma membrane redox system (PMRS) export electrons from NADH, recycling it into NAD+. This process is only very active in cells which have been taken over by DNA-damaged, non-OXPHOS mitochondria, but their outer surfaces are little hotspots of electron dumping.

What do these electrons do? Well, for one, they combine with oxygen molecules – which are abundant in any of our living tissue – to create reactive oxygen species (ROS): more free radicals. So you have the Rube Goldberg system outlined above whereby a few free radicals have caused a cell to become an ongoing, major exporter of free radicals into the surrounding environment. These will make life unpleasant for surrounding cells, but that is most likely not the real problem. ROS just can’t travel far enough to explain how a corrupt 1% of our cells can cause a large fraction of the difference between being young and being old.

A more likely target for all the newly created ROS is cholesterol. Cholesterols, such as low-density lipoproteins (LDL) are used everywhere in the body and travel widely. If ROS reacts with nearby LDL – and there will always be nearby LDL – to form damaged, oxidized cholesterol, that damaged cholesterol can then be incorporated into and further damage biochemical processes throughout the body. For example, its effects on our arteries is well known:

In conditions with elevated concentrations of oxidized LDL particles, especially small LDL particles, cholesterol promotes atheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease.

There are many other ways in which accumulations of oxized cholesterol can send biochemical processes awry. This, then, seems to be a good candidate for the plausible, systematic method by which a small number of cells can work such varied damage upon your entire body.

Aubrey de Grey has proposed an engineering solution to this problem, based upon this way of looking at it. That is to go straight to the root, and get the OXPHOS process working again by (a) moving mitochondrial DNA into the nucleus, and (b) ensuring that the necessary proteins can make it from the nucleus back into the mitochondria where they are needed.

As usual, we’re lucky – evolution has done the hardest part of this for us already. Mitochondria are very complex — there are about 1000 different proteins in them, each encoded by a different gene. But nearly all of those genes are not in the mitochondrion’s DNA at all! — they are in the nucleus. The proteins are constructed in the cell, outside the mitochondrion, just like all non-mitochondrial proteins. Then, a complicated apparatus called the TIM/TOM complex (no kidding…) hauls the proteins into the mitochondrion, through the membranes that make its surface. Only 13 of the mitochondrion’s component proteins are encoded by its own DNA.

This gives us a wonderful opportunity: rather than fixing mitochondrial mutations, we can obviate them. We can make copies of those 13 genes, modified in fairly obvious ways so that the TIM/TOM machinery will work on them, and put these copies into the chromosomes in the nucleus. Then, if and when the mitochondrial DNA gets mutated so that one or more of the 13 proteins are no longer being synthesised inside the mitochondria, it won’t matter — the mitochondria will be getting the same proteins from outside. Since genes in our chromosomes are very, very much better protected from mutations than the mitochondrial DNA is, we can rely on the chromosomal copies carrying on working in very nearly all our cells for much longer than a currently normal lifetime.

On March 22, 2010, posted in: Articles, Oxidative Stress by admin

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