Power Struggle

November 9, 2017
November blog image_11.9.17

Source: Professors P. Motta & T. Naguro/Science Photo Library

Power takes many forms. In physics class, we might think of it as what it takes to move a mass of X from point A to point B, over a certain time; a rate of work. Or in politics, perhaps it is the influence an individual or institution leverages to achieve its objectives.  But when it comes to biology, the “seat-of-power” resides along membrane leaflets within ancient microbially-derived organelles, and for those of us within the animal kingdom we call them “mitochondria.”

Typically, our appreciation of these biologic relics might include a biochemistry class and a vague memory of so called “electron transport.” Or perhaps we read about their role in helping us simplify the study of human evolution.  In most animals, only the mother’s mitochondria persists because those within sperm cells self-destruct immediately after conception. This, combined with the fact that mitochondria contain small but readily-sequenceable genomes (only 37 genes), simplifies their use in tracking our evolutionary lineage all the way back to the so call original “Eve” of humanity.  And while these recollections are both correct and impressive, they under emphasize the centrality of mitochondria in the story of life.

So, let’s back track just a little more. How life started remains one of our ultimate scientific mysteries.  What is known is that as the earth slowly cooled, chemical diversity began to grow, and by the hand of fate (or for some the divine) the first stages of life on earth seem to have appeared about 3-4 billion years ago.  But these were simple creatures, so to speak, single cell organisms and they remained the sole masters of our young earthly realm for at least another billion years. Then, by what can only be imagined as a remarkably awkward forced marriage, two very different type of bugs began to live intertwined and over time they became completely interdependent on each other. One of them, was probably a so called α-proteobacteria, and it began to help the other contend with the increasing concentrations of oxygen (a highly reactive element) that was then accruing in earth’s evolving atmosphere.

This moment of bug-to-bug “conception” may have been the single most important event in enabling everything interesting in biology that has happened since. As it is now believed, that every eukaryotic organism (the complex cell types representative of everything except bacteria) has evolved from this single synergistic pair. A postulate that, while hard to prove, has a compelling genetic innuendo.

Over the millions of years since, all bacteria have remained just that, simple.  But all forms of life that were derived from this “awkward hybrid,” have had the ability to manage and exploit the remarkable reactivity of oxygen. And only they have been able to evolve into the huge biologic bounty of complex life spread across Earth. From that “little bug that could deal with oxygen,” we are gifted with today’s mitochondria, and the power to enable all biological diversity that surrounds us.

Is it really all about power? It would seem so. As mentioned before, mitochondria provide the basis for aerobic respiration, which when compared to fermentation, produces about 13x more ATP – the primary energy storage/utilization molecule of life on Earth. The number of mitochondria vary widely by cell type with zero in red-blood cells to about 2,000 in liver, but generally, mitochondria comprise about 1/5th of the total mass of a given cell. Each have their own small genome (mtDNA), and each can have up to 10 distinct copies of it.  They retain the ability to transcribe and translate their mtDNA locally. Yet to conduct business, the proteome of mitochondria can have upwards of 600 proteins; the vast majority are now encoded in the nucleus as a derivative of getting them away from the consequences of being too close-to-the action in these little powerhouses.

Within these little organelles, some truly high-powered energetics that operate on a nanoscale are in-play. By shuttling electrons down a series of complexes (remember: electrical power is the ability to move electrons down a conductor), the mitochondria create an electrical differential between the two sides of a bilayer lipid membrane; and this potential difference rivals the electrical potential released in a lightning bolt.  And it is this electrical potential between the mitochondrial membranes that is then re-harvested by something called Complex V to drive the coupling of high-energy phosphate bonds within ATP.

But perhaps most remarkable of all are the dynamic genetics and resulting biogenesis of mitochondria.  Not surprisingly, mistakes can occur during the acrobatics of making high energy molecules, and as a result, we don’t get those high-energy electrons where we want them.  Instead, they arc to generate free oxygen radicals.  And, as every health magazine will jump in joy to share, these are highly toxic, to local mtDNA (and everything else). Thus, the suggested nutritional craze for anti-oxidants.

To keep the collateral mtDNA mutations at a minimum, mitochondrial genes not requiring local expression have been, over the millennia, shuttled to the nucleus. But those remaining within mitochondria do accrue damage. If they can’t be repaired, the individual mitochondria themselves self-destruct and are, hopefully, backfilled by the on-going replication (biogenesis) of neighboring and presumably unmutated (or at least less so) mitochondria.

The fact, that within a given cell, a set of genetically diverse mitochondria exists is not often considered enough in biology/medicine. But heteroplasmy (a mixture of genetically different mitochondria) is found in about half of the egg cells taken from the same ovary and similar findings are seen in many other cellular settings. Recently we have begun to think of the diversity of our microbiomes (the bugs in our gut, on our skin, etc.) and the impact that they have on our health and wellness.  These findings suggest that another type of “microbial” genetic diversity, in this case intracellular, is also subtlety in play – kind of like a “mitobiome.”

While “life is good”, or at least young, generally all remains fine. But over time, the tides begin to turn as the number of effective mitochondria begin to decline.   As the cohort of mitochondria begin to collectively fail within a given cell, this triggers apoptosis which removes that cell from a tissue before additional oxidative damage could have brought about other outcomes, such as malignant transformation. Slowly, these processes result in age-associated tissue atrophy. Because the individual faulty mitochondria most often eliminate themselves before their inadequacies can trigger defects at the whole cell level, we don’t easily detect high levels of mitochondrial mutations across aging tissues. But there is a high cost for such purification – slowly over time, the reservoir of undamaged mitochondria gets too low, resulting in cellular loss and the gradual loss of tissue function. With that comes aging and eventual death.

So, from the ultimate energetic gifts of our mothers, we arrive, travel, experience and (hopefully) contribute back to our world, but as with all power it is consumed by use and declines over time. It is purely up to each of us, the recipients of these magical engines, to ensure that their amazing efforts are not wasted.