Presumably, as you read this sentence, you've already moved beyond the adolescent stage of your life. This means that your mitochondrial repair mechanisms have already been largely compromised. Therefore, all the mitochondria in your nerves and muscle cells are quietly turning to toast! As these organelles transform from the proverbial ashes to dust and entire cells are sent to apoptotic death, what's left of your lung tissue must compensate for what's left of your heart muscle. The rate of mitochondrial incineration is dictated in part by metabolic rate, determined in part by thyroxin (T1, T2) and in part by the excess of calories swallowed but not subsequently consumed during exercise. Does this observation merely engender cognitive dissonance?
Yet there is hope. And we need your help to find the answers. Please read through the rest of this web site and work toward finding the answers we need.
For the recent information about mitochondria-related disease see Douglas C. Wallace, "Mitochondrial DNA in Aging and Disease," Scientific American, pp. 40-47 (August 1997) or visit the Human Mitochondrial Genome Data Base [1995-97] at Emory University's Center for Molecular Medicine MITOMAP.
Another pointer to recent material on Mitochondria follows:
MITOCHONDRIA AND AGING*
According to the central dogma of mitochondrial evolution, several billion years ago, a number of bacteria with a talent for converting glucose molecules to ATP for their own personal use (by means of the Krebs Cycle) were engulfed by a much larger eukaryotic cell with a talent for mobility (and thus a more efficient means for acquiring nutrition beyond its immediate limited substrate) which, of course, the procaryotic bacteria did not enjoy. By mutual consent, a partnership was formed in which genes were exchanged between the organisms and a strong mutual dependency was established: The large mobile cell sequestered genes from the bacterium within its more well-protected nucleus distinctly created for that purpose, while this eukariotic cell also formed a set of distinctive proteins for transporting ATP molecules through the outer membrane of the bacterium and into the cytoplasm of the eukaryote (not a requirement of the isolated bacteria) where they could be utilized throughout the larger cell for its own purposes. One of the principal members of this protein family is called Adenine Nucleotide Translocator (ANT). (Apparently, glucose itself could be diffused into the bacterium without any special requirement for a carrier protein, like insulin.) In exchange, the bacteria received the benefit of a more stable source of nutrition. This symbiotic relationship turned out to be so mutually beneficial that the larger cell provided the environment for a whole "colony" of such bacteria which now inhabited its cytoplasm. These bacteria are now referred to as mitochondria, since they are no longer autonomous infectious agents.
In time, feedback mechanisms were created between the nucleus and the mitochondria to trigger their fission whenever the output of ATP in the cytoplasm fell below a certain threshold concentration and while glucose was still present in sufficient concentration to allow additional mitochondria to exploit it.
How does aging enter the picture? It is speculated that aging may be mediated, in part, by the accumulation of random mutations in the mitochondrial DNA which is more sensitive to uv radiation and chemical mutagens (free radicals), since mtDNA doesn't have the benefit of negatively charged histone proteins to protect it, as nuclear DNA does. In the process of manufacturing ATP, mitochondria with broken membranes can spew out astronomical numbers of reactive oxygen molecules called "free radicals." In the July 1997 issue of Nature Genetics, Prof. Douglas C. Wallace of Emory University School of Medicine (now at the University of California at Irvine) explains that mtDNA may account for more than rare diseases. If mtDNA damage accumulates sufficiently, the mitochondria may have more trouble cranking out ATP. Brain, heart, and muscle cells, which require the most ATP start to falter.
Older people may first notice a lack of zip in their walk. Wallace says, "I've felt for years that what older patients were really telling me the same thing we were seeing in the laboratory. The loss of energy is what really robs older people of their dignity. Protecting one's mitochondria from mutation or replacing bad ones with good ones might allow people to mitigate some of the debilitating effects of old age. Muscle fatigue, heart failure, and memory loss may all stem from mitochondria that can't keep up with the cells' energy requirements. (How do eggs shield their mitochondria from degradation? Remember the original "Eve" hypothesis?)
Other scientists remain cautious about accepting this theory, however. Wallace and other scientists have demonstrated that animals, including humans, do accumulate mitochondrial mutations as they get older. To say that those mutations cause old age remains a leap--at least for now--until mouse genetic engineering experiments are done to transfer young mitochondria to old mice to see what happens. Ultimately, however, even perfectly youthful mitochondria in centenarians wouldn't permit immortality, since other defects in the nucleus might tend to overtake the cells' ability to manufacture replacement proteins for growth and repair. Still reversing the energy drain would provide a significant advantage for slowing aging. In conclusion, Wallace says, "We're looking for the mechanisms that cause day-to-day degeneration. That's what we want to solve."
To: scoles@grg.org
Date: Fri, 13 Feb 1998 12:55:09 +0200
From: Kvitko <biogeron@biobel.bas-net.by>
Subject: Comment on the idea of transfer of young mitochondria to old mice
From: Dr. Oleg V. Kvitko February 13, 1998
Institute of Genetics & Cytology
National Academy of Sciences of Belarus
Akademicheskaya Str. 27, Minsk 220072, Belarus
Tel: (375) (17) 268-5190; FAX: (375) (17) 268-4917
E-mail: biogeron@biobel.bas-net.by
Dear Dr. Coles:
In "A Word about Mitochondria" the idea has been proposed that transfer of young mitochondria to old cells could "provide a significant advantage for slowing aging." But the result of such an experiment might be quite the opposite. As is widely accepted, free radicals damage different parts of the cell (not only mitochondria). Transfer of the young mitochondria could increase not only energy production, but free radical production also. That might lead to increased damage of other cellular molecules (including nuclear DNA) and, consequently, not slow but accelerate the aging process. Age-associated decline of ATP production in mitochondria is compensated (at least partly) by the increased glycolysis. Age-associated shift from aerobic to anaerobic metabolism might evolve as a protective antiradical mechanism. In this connection it would be interesting to remember that such a metabolic shift also happens in cancer cells.
Very truly yours,
Oleg Kvitko.