On the Beauty and Power of Mitochondria

One fundamental characteristic of current civilization is selfishness permeating all levels and spheres of human existence: from the individual perceptions of being, to the social implications of coexisting, to the economic theories of managing and turning co-existance into a profitable network, to the environmental issues of ecologic co-dependance and to the scientific innovations that promote knowledge.  In all of the aforementioned fields and in even more, selfishness has governed and spawned most of the theories and practices that we today encounter.

This solipsism, this egomania, this perception that only I and Mine exist and are worth serving, saving and caring for, has already created huge financial problems with the 2008 crash. It is creating even huger environmental problems and no one can confidently predict if, and how we are going to be able to resolve and restore balance in our cosmos.  In other words, this approach, though a sometimes admirable driving force of the western world, has an innate limitation: It considers expansion of "self" and exploitation of others as limitless.

But since space exploration is underdeveloped, for the next decades we are bound to live in a "sphere" called earth, a world whose limits are well defined and known, a limited world, not a limitless one. When expansion has reached exhaustion, when new sources, ideas, innovations, markets, and technological breakthroughs are hard to find, when "self" has expanded to such a degree that it can no longer transpose or transfer or dump its problems into new ground, into fresh "others," once self has become almost "everything," at least everything it knows and owns of the cosmos, then "self" has to encounter all of the problems of the "others" that it has by now conquered, phagocytosed, incorporated. And when this time comes, it has only two options (actually only one, but for the sake of argument we'll propose that they are two).

One is to try to survive by metamorphosing, to become more introverted, reinvest some of the dynamics of the expansionistic aggressiveness into solving internal problems by creating more detailed and extensive networks and regulations and attempting to stabilize and redefine this uncontrollable "self." This is a model of internal expansion, of expansion within one's self, an introspective approach.

The other is to attempt to expand further at the same or higher rate than previously when expansion is no longer viable, and ultimately collapse into itself like a black hole.

There are many paradigms that attest to the nature and outcome of expansion in a limited world. It begins with marvelous aggression, almost unobstructed, until it reaches its limits. Historically, all empires collapsed from within when they could no longer sustain expansion. Rome lasted longer because it transformed some of its aggression into administration. In cosmology, if expansion speed does not overcome escape velocity, the universe will contract (and finally collapse), possibly back into a universal pre-Big Bang state.

In biology, a cell culture grows geometrically until the nutrient substrate is exhausted. Then the culture starves to death and diminishes (in a sense collapses into itself) until the proper ratio of available nutrients is restored. In the sociologic and financial Malthusian model, overpopulation can exhaust the planet's available resources and lead to war, famine or both, again in a sense collapsing unto itself (of course Malthus took into consideration only overpopulation and not also, as he should have done, overexploitation).

This is what universally happens when expansion is not sustainable but is still perceived as indefinite: collapse.

But what about medicine?

Medicine, and biology in general, is fraught with selfish perceptions. From the Darwinian survival of the fittest to the neo-Darwinian selfish gene, from anti-drugs (antibacterial, antiviral, anticancer, etc.) to a genetically governed world, all these disciplines teach us is Self. Self is good and must be preserved, non-self must be destroyed or controlled. Even cancer — which is a bizarre, immortal, yet often lethal and ultimately self-destructive expression of self — is treated by medicine as a non-self, as the enemy that must be destroyed. Since the human body is limited and well defined, expansionism is expressed in exerting control and destroying the others. But even this expansion of Self has limitations;  As the immune system very well knows, the notion of Self in medicine cannot be taken literally.

Our genome constists of incorporated, inert (most of the times) viral genetic material. Our intestinal flora consists of non-self bacteria, vital for our survival and well-being. And our own cells contain cell organelles that billions of years ago were non-self and still are not completely subjected to our cellular government of the nucleus.

We call them mitochondria. They are our power plants. They are matriarchally bestowed on us by inheritance. They have their own DNA (mtDNA) which is independent from our "core" DNA, the biological essence of our being and fate, as "macho" medicine wants us to believe. They are not just organelles that are centrally and absolutely governed by core DNA. They are essentially symbiotes, viscelarized in our cellular ancestors billion of years ago, giving us now the energy we depend on to live.

When needed, they multiply to provide our tissues with additional energy. But their DNA is also more sensitive than core DNA. They don't have the complexity and the longitude of the core DNA repair system. So they get damaged more easily. And when they get damaged or depleted they can lead to or get involved in any type of noninfectious disease states one can imagine. Imagine a factory without power, or experiencing a shortage of power. It can be completely dysfunctional, or the administration can choose to shut down sectors to save power for the most important ones. Some or all workers in the factory will work in the dark. Occupational accidents will happen. If there is a general power shortage, the factory, no matter what the administration decides to do, will become dysfunctional or ultimately shut down. Our civilization will be seriously impaired or shut down if faced with serious energy shortages. There is no need to argue whether our body will definitely do the same: deteriorate or die.

There are thousands of mitochondria in each cell. Each mitochondrion in turn contains multiple copies of mtDNA. This variable mitochondrial numerology has many implications and complications for health and for disease expression,  and severity. One has to understand the complexity and the diversity of mitochondrial involvement in health and disease states. Mitochondrial deficiency, damage, inefficiency, mutation or any combination of the same does not manifest itself homogeneously, and may effect certain cells or tissues of the body, or be systemic or even catholic. It may be sudden or slow or cataclysmic or acute or degenerative; episodic, chronic or both; triggered or remain "dormant," with mild or severe symptoms or no symptoms at all, or sometimes subclinical symptoms that may not be necessarily associated with a disease state, such as fatique, restlessness and vomiting. It might contribute to other disease states or be affected by other disease states. It might even be associated with dys-motility, migraine, depression, anxiety, mood or other psychiatric disorders.

In depression, especially in depression with somatization, low energy production and mitochondrial involvement has also been indicated. The reverse process — that is, whether depression somatization causes mitochondrial dysfunction, which in turn aggravates depression — should be also examined, as this loop is in accordance with the "positive feedback" depression, low self-esteem and reduced physical mobility progression.

And it is not only about noninfectious diseases. Infectious diseases can also cause direct damage to mitochondria, complicating things even further. And there has been a novel discovery indicating also that mitochondria play a vital role in immune response, and thus that mitochondrial are vital in fighting off infections and especially RNA-Viral infections such as flu, hepatitis, West Nile Virus, SARS (and possibly the so-called HIV infection?). A protein named MAVS (Mitochondrial Anti-Viral Signaling protein) located in mitochondrial membrane plays an initial role in triggering immune response against viruses.

On the other hand, one of the key elements of the biochemical chain of events that comprise an immune response (co-triggered as suggested by MAVS) is interferon. Interferon has the ability to inhibit mitochondrial DNA expression and therefore function. Furthermore there has been some mitochondrial involvement indicated in autoimmune diseases.

So, in this long chain of events and counter-events, of effects and counter-effects, it is very hard to distinguish cause from effect, first from second. The mitochondrial realm is not governed by some linear, strictly deterministic rationale, but rather works in circular patterns with intertwining positive and negative feedback mechanisms. It is not about intervention, it is about balance. It is not about attacking or prohibiting. It is about regulating, coordinating and tuning. It is not only about finding and defining. It is about understanding the big picture. And these are tasks that the overspecialized lab-rat scientist will fail to address over and over again, tasks that Big Pharma will either ignore or conceal.

For reasons of achieving better understanding, biochemical events are more often than not described as linear, and organelles and cells are described as if static. The universally accepted truth is that most systems are not static. They are dynamic. The cell world is fluid, a sea. Shape-shifting and motility occur over time. The questions of shape and motility play a vital role in biological events and have not been properly addressed so far. Mitochondria are mobile elements in a mobile world. The mitochondria do not eternally retain a morphological integrity. They fuse with each other, exchanging components and materials, in a cellular ritual that one could describe as "mitochondrial sex." This is the actual world of mitochondria, not a textbook schematic or electron microscope picture. It is poetry in motion.

Mitochondria are pivotal, critical, beautiful. They are life-givers, life-providers. One could say that mitochondria are life. And as expected, as in all things living, they are also death.

Mitochondria are associated with cell apoptosis. Mitochondrial damage is not only associated with disease but also with aging and ultimately death. There can possibly be some events of cataclysmic mitochondrial damage and some inherent mitochondrial diseases that can give a kid the mobility and energy of an elder. But usually, due to the complexity of the mitochondrial system, damage caused by drugs, toxins, age, and malnutrition are accumulating over time before they reach a threshold and start to produce evident or measurable health effects.

Let's examine some of the things that can make our mitochondria and us sick, old and ultimately dead.

Free radicals: drugs, pesticides, smoking, chemicals, environmental toxins can damage our mitochondria. As mitochondrial DNA is more susceptible to damage, it has been suggested that chemotherapy and radiotherapy can cause point mutation of mtDNA.

Methotraxete, a potent chemotherapeutic and rheumatic agent, exhausts folic acid and subsequently purines, inhibiting DNA and of course mtDNA synthesis, leading progressively to mitochondrial depletion.

Another agent under investigation for the treatment of cancer in combination with chemotherapy is buthionine sulfoximine, a synthetic amino acid that inhibits gamma-glutamylcysteine synthetase, thereby depleting cells of glutathione. Glutathione is a metabolite that plays a critical role in protecting cells against oxidative stress in free radical-induced apoptosis. Through extensive depletion of glutathione, buthionine sulfoximine damages muscle cell mitochondria and leads to sketetal muscle degeneration. The damage can possibly be prevented by co-administration of glutathione monoester. 

Mitochondrial damage does not only involve cancer chemotherapeutics. Another class of chemotherapeutics that block essential cellular functions, the AIDS chemotherapautics and especially RTIs (Reverse Transcriptase Inhibitors), cause mitochondrial depletion or damage. The dreaded and disfiguring lipo-atropthy is perhaps the most obvious RTIs side effect on mitochondria. There are possibly many, many, many more RTIs-related mitochondrial damage that are there to be explored and addressed.

This is a possible side-effect drug profile that was from the very beginning obvious to anyone who had the capacity to think straight. RTIs inhibit reverse transcriptase. Mitochondria employ reverse transcriptase. Thus, RTIs would logically damage mitochondria. Yet, despite that, relatively little research was done on RTI and mitochondrial damage in relation to research done on RTIs therapeutic benefits. Why is that?

What about other "virus specific" antiviral treatments? Ribavirin, used in hepatitis C treatment in combination with RTIs, work synergistically in inducing increased mitochondrial toxicity.

But it is not only antiretrovirals that damage mitochondrial DNA. Let's not forget that mitochondria is of bacterial origin, so antibiotics seem perfectly able to undo them. And they do. Antibiotics called aminoglycosides used to treat chronic bacterial infections such as tuberculosis may attack mitochondria in people that specifically have an MT-RNR1 gene mutation and cause deafness. This is of course a somewhat rare but very real adverse drug reaction.

Another class of antibiotics, sulpha compounds like cotrimoxazole (Bactrim, Septrim), used until recently in acne treatment, block the synthesis of tetrahydrofolic acid, the metabolically active form of folic acid, and subsequently the synthesis of purines, arresting mitochondria from producing DNA and gradually depleting them. Heavy metals can do the same.  

Other antibiotic classes like fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid have been also shown to impair mitochondrial function.

Valproate, an anticonvulsant and mood stabilizer, can damage mitochondria, and some statins can too. Natural neurotoxins, some fungal toxins and chemicals such as MPTP and the insecticide rotenone can also damage them.

Now imagine this: An AIDS patient is taking RTIs for AIDS, radiotherapy for persistant KS (Kaposi's Sarcoma), chemotherapy and radiotherapy for Non Hodgkin's lymphoma, and different classes for opportunistic infections. All of the above cause mitochondrial damage through different metabolic pathways.

Or imagine any other combination of the huge array of mitochondrial killers in a body. This a biochemical havoc, a mitochondrial genocide. Now add to this free radical and toxic accumulation and what do get? A dead or at best chronically impaired patient. Even if anyone was to survive the underlying medical conditions, none can survive for long without mitochondria.

In the beginning of the previous century, an eminent biochemist and Nobel laureate, Otto Warburg, made an elegant hypothesis. He proposed that cancer derives from cells shutting down their aerobic respiration and turning anaerobic; that in a sense the cell and mitochondria are dissolved, a forced divorce. Heinrich Kremer revitalized the theory and expanded it to AIDS, to face fierce critiques and prosecutions.

It is obvious that our fragile mitochondria are absolutely essential and are involved in an incalculable number of disease and health conditions that have been ignored by orthodox research.

There have been some treatments proposed to avoid, limit, repair or reverse mitochondrial damage, to avoid or limit disease conditions, and to promote wellbeing and perhaps longevity. The use of antioxidants seems rational, since free radicals damage mitochondria as well. There should be no arguing over this. Free radicals cause damage, antioxidants scavenge them. The real issue is an issue that occupies conventional  -- and should also occupy alternative -- disciplines of medicine: how to deliver substances to where they are essentially needed. The issue of antioxidants and supplementation should be an issue not of pharmacology in general but rather an issue of pharmacokinetics.

Bruce Ames, an eminent molecular biologist and the inventor of the Ames test, has been studying the process of aging for years; he actually grew old studying the state of oldness. There are few who have studied mitochondrial involvement in aging as thoroughly  as Ames. And he is still at it. He supplemented rats with a combination of two common dietary supplements, acetyl-L-carnitine (an acetylated form of L-carnitine that transports fatty acids from the cytosole to mitochondria, where they metabolized for the production of energy) and alpha-lipoic acid, a known antioxidant. The results were impressive, as Ames has narrated:

"With the two supplements together, these old rats got up and did the Macarena. The brain looks better, they are full of energy, everything we looked at looks more like a young animal... We did two different tests for cognitive activity in rats, and in both it made a big difference to feed them this mixture. Memory degenerates with age, and this makes them better." 

Two other nutrients, vitamin B-1 (thiamine) and/or B-2 (riboflavin) are required cofactors for the conversion of adenosine diphosphate (ADP) into the "bioenergy currency" adenosine triphosphate (ATP) have been suggested to be mitochondrial friendly. Furthermore, they have been suggested to repair certain types of mitochondrial damage. Antioxidant Vitamin E and ATP recharger co-enzyme Q-10 might also have applications to prevent mitochondrial damage and promote mitochondrial function.

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I have referred to expansion vs. exhaustion models and suggested that they are universal. Health clearly expands to the point where mitochondria (energy) are exhausted. After this point it collapses. The suggestions of mitochondrial supplementation are just rough drafts toward a future medical science that will promote energetic living instead of pathetic being — will adopt a dynamic interpretation of cellular life instead of a static one. There is so much we don't know about mitochondria, cell symbiosis and balance that we can only dare to make suggestions on how to treat them and how their abuse is jeopardizing the health of our generation and future generations.

The steady, stable, well-arranged and totalitarian universe, governed by law, God, principle, DNA, kings, priests, tycoons and specialists has expanded so much that it has already reached exhaustion. It is time for new, dynamic models to appear in all fields, and especially in the most stagnant of them, medicine. A quantum revolution in biology has to come about soon. And we have to better understand and accept the meaning of the word equilibrium: both sides of the scale in balance.

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