The paper this post is based on can be found here. Be warned, its pretty dense. The author, Doug Wallace, is one of my favorite researchers, and I'll be posting more from him in the future and attempting to translate it into a more digestible form.
This post contains a summary of mitochondrial DNA vs Nuclear DNA, hapolotypes, and discusses Wallace's work looking at Traditional Chinese Medical herbs as potent regulators of mitochondrial function.
Mitochondrial health and bioenergetic capacity as component of the future paradigm of health - Picture courtesy of Doug Wallace
Did you know that we have multiple genomes in our body? Our nuclear DNA (nDNA) is what we usually think of (the type of DNA mapped by the human genome project that exists in the nucleus of our cells) but, we have a distinct set of mitochondrial genes that exists separately from our nDNA. We also have a massive amount of highly dynamic microbial and viral DNA that exists within us that dwarfs the number of genes we have in our nDNA, but thats for another post.
This article entitled "Mitochondria as Chi" outlines some of the factors in mitochondrial dynamics and the interaction between mtDNA and nDNA. Note, that if this title turns you off instinctually, its actually written by the world's top expert on mitochondrial disease, Doug Walace. Its a pretty technical paper but worth the read if you're interested in this kind of thing.. You have thousands of mitochondria PER CELL, and they produce the energy currency of the body. While much of scientific community has been focused on looking at nuclear DNA as the cause of disease and health, mitochondrial DNA has been somewhat overlooked in the larger picture. Perhaps this is because it is a much smaller genome, only coding for 13 proteins in the mitochondria. The nuclear DNA codes for a much larger portion of the mitochondrial complex, so it would seem it would be more important, right?
Perhaps not. mtDNA mutates at a much faster rate than nDNA, allowing much more rapid adaptation to the environment. Groups of people that evolved around the equator have specialized and different mitochondrial function than those evolved in a cold environment. In fact, your mtDNA is how your maternal ancestry is determined in genetic testing, as you inherit mitochondiral DNA only from your mother, and the set of specific mutations in your mtDNA can be linked to a larger group (called a haplogroup) that is associated with the environmental adaptions to a specific place on the earth. People on the equator need to produce less heat so their mitochondria is more tightly coupled, producing more ATP and less heat. People in cold environments need to produce more internal heat, so they have more loosely coupled mitochondria, producing more heat and less ATP. While it might seem like people near the equator have a greater advantage from more ATP production, the heat produced (which is emitted as infrared LIGHT) is absorbed into the surrounding cellular water, splitting it into an electric dipole a la the work of Gerald Pollock, conserving the energy released as DC electrical current via the photoelectric effect.
This paper outlines how different haplogroups come with different health risks and protective factors, for things like Alzheimer's, Parkinson's and diabetes, and providing different athletic abilities. The bioenergetic quality and capacity of our cellular metabolism can influence alot!!
Due to the fact that our mtDNA mutates so quickly, targeted destruction of poorly functioning mitochondria is highly important (apoptosis). We have a built in scanning system that determines which mitochondria need to be destroyed, and they turn over on a pretty regular basis. However, if there is too much damage from ROS (free radicals) and not enough mitochondrial integrity, that scavanging system begins to fail and we accumulate more mutated mtDNA. With such a high volume of mitochondria per cell, it is important that they are "on the same page" so to speak, and work well together. With higher amounts of mitochondria containing mutant mtDNAnare mixed in with the original DNA, chaos begins to ensue and the bioenergetic output diminishes. This is called heteroplasmy, and one of Wallace's critical discoveries is that different disease states are associated with different rates of heteroplasmy. This occurs both in sex-cell lines in oocytes, and the most deleterious mutations are selected out before they mature, and occurs in somatic cells as we age or are exposed to environmental insult.
"A synthesis of these specific mitochondrial genomic concepts provides a plausible model for the predisposition toward and development of age-related diseases. In this scenario, an individual is born with an initial mitochondrial energetic capacity based on inherited variation in nDNA- and mtDNA-encoded mitochondrial genes. Relevant nDNA variation could affect mitochondrial energetic output, antioxidant defenses, apoptotic thresholds, mitochondrial biogenesis and turnover, etc. As the individual ages, somatic mtDNA mutations arise in post-mitotic cells and stem cells, and the individual somatic mtDNA mutations become clonally amplified within each affected cell, both post-mitotic and stem . The clonal amplification within the cell either is the result of intracellular genetic drift during the turnover of mitochondria during successive cell divisions or, alternatively, is the result of the selective amplification of the mutant mtDNA . As the mutant mtDNAs accumulate, they progressively erode the individual cell's energetic capacity. Ultimately, cellular energetics drops below the minimal output necessary for normal cellular and tissue function and survival. This leads to a decline in organ function, loss of cell numbers, tissue failure, and an aging phenotype"
Wallace ends this paper with a discussion of how Asian herbal remedies are likely candidates for systeminc mitochondrial enhancers, and how based on their assay techniques, the found that Ginkgo Biloba did have a system mitochondrial boosting effect. Since Chinese medicine is based on the concept of healthy Chi, or life force energy, the analogy can be made between it and the western perspective of mitochondrial function. This paper was written in 2008, and alot more research has been done since then. We now know alot more about how mtDNA and nDNA communicate, and mitochondria act not only as energy producers, but also energy sensors. This ties the eastern concept of chi not only as an energy source, but also as a factor in sentience. Personally, I love seeing this type of comparison and synthesis when its done in a well grounded way. Mitochondrial dynamics might provide a way to understand traditional remedies that "just seem to work."
"How might we jump-start the search for mitochondrially active backbone compounds to treat the age-related diseases? One promising approach might be traditional Asian herbal medications. Unlike drug development in Western pharmacology, which requires a known drug target around which the drug is developed, traditional Asian pharmaceuticals were discovered by trial and error, on the basis of what made the patient better. This trial-and-error approach to drug development is inefficient but it is paradigm blind. If mitochondrial dysfunction is as important a factor in age-related diseases as proposed in this essay, then Asian herbal medications should be as likely to have targeted a mitochondrial energetic function as a tissue-specific structural function. If so, we might be able to identify active mitochondrial backbone drugs by screening traditional Asian therapeutics for those that modulate mitochondrial function. To detect mitochondrially active compounds, we have assembled a mitochondrial cDNA expression array, the MITOCHIP, which interrogates ∼1000 genes involved in mitochondrial energy production, ROS biology, and apoptosis. We have tested the veracity of our hypothesis that Asian medications might target mitochondrial function by testing the effects of Ginkgo biloba leaf extract on mitochondrial function in cultured cells. G. biloba did indeed alter mitochondrial gene expression, appearing to modulate mitochondrially associated apoptosis (Smith et al. 2002). The association between Asian herbal medications and mitochondria has been further enhanced by the discovery that the potent antimalarial Artemisinin (quinghaosu) acts on the mitochondrion (Li et al. 2005) and the observation that, after screening 2490 compounds for the effects on mitochondrial gene expression and physiology, the Chinese herbal derivative deoxysppanone B was found to act through microtubules to increase OXPHOS and decrease mitochondrial ROS (Wagner et al. 2008)."
