|Mitochondria and Aging|
Mitochondria are central components of our cells that generate the majority of our energy from nutrients. But their dark side is that, through their normal activity, they generate unstable chemicals that harm both the mitochondrion itself and other components of the cell. This resulting damage is thought to play a important role in aging, and many labs are developing techniques for attenuating and reversing this damage. If mitochondria play such crucial roles in aging, then these discoveries could very possibly lead to the first bona fide anti-aging therapies.|
What are mitochondria?
Mitochondria are double-membrane organelles, typically rod-shaped, and about 1 micrometer in length. The number of mitochondria in a cell is determined by the cell's specific function and energy needs. Cells such as heart muscle cells have many mitochondria and red blood cells have none. The inner membrane is folded into "cristae" that project into the region inside the inner membrane called the "matrix." The area in between the inner and outer membrane is termed the "intermembrane space." Each mitochondrion contains 4 to 5 copies of its own circular DNA (mtDNA), which encode ribosomal RNA, tRNAs, and a few of the protein components of the electron transport chain. The rest of the mitochondrial proteins are encoded in the nucleus and imported to the mitochondrion via specialized protein import processes. It is thought that mitochondria were once prokaryotic organisms that were engulfed by our eukaryotic ancestors, subsequently forming a symbiotic relationship. The eukaryotic organism provided protection and nutrients for the prokaryote, and the prokaryote provided a means of generating energy more efficiently using oxygen. This evolutionary process is termed "endosymbiosis."
Function: Generation of Useful Energy via Aerobic Respiration
Mitochondria perform "aerobic respiration," a process that generates the energy molecule ATP from nutrient molecules using oxygen. This process is critical in that ATP constitutes one of the body's principal usable energy reservoirs. Three key components of aerobic respiration are 1) glycolysis, 2) the Kreb's cycle, and 3) the electron transport chain (ETC). In glycolysis, one molecule of glucose is split into two pyruvate molecules, generating 2ATP and 2NADH molecules. Pyruvate is then converted into acetyl-CoA (acetyl coenzyme A), which enters the Kreb's cycle to generate 1 ATP, 1 FADH2, and 3 NADH per acetyl-CoA. The NADH and FADH2 molecules serve as "electron carriers" by transferring electrons derived from glycolysis and the Kreb's cycle into the ETC. In the ETC, proteins in the inner membrane use these electrons to create a pH gradient across the inner membrane; the membrane proteins pump protons from the inner matrix into the intermembrane space. This gradient serves as an energy reservoir that drives the creation of ATP as protons are pumped back into the inner matrix through a membrane protein called "ATP-synthase." For each glucose molecule, a total of 32 ATP are produced via the electron transport chain, in addition to the 2 from the Kreb's cycle and 2 from glycolysis. This yields a grand total of 36 ATP produced via aerobic respiration. Therefore, from one molecule of glucose, the presence of mitochondria increase the usable amount of energy from it by 34 ATP, or 1700%, over glycolysis alone.
Mitochondrial Theory of Aging: Does ROS Generation Initiate a Vicious Cycle?
An unfortunate side effect of aerobic respiration in mitochondria is that the electrons donated to the ETC can often "leak out" and, rather than driving the creation of the pH gradient, can instead go on to form unstable molecules called reactive oxygen species (ROS). Unstable ROS are capable of damaging many types of cellular components, and it is thought that the damage that may acculumate over time from ROS generated from aerobic respiration may play a significant role in aging. Given that mitochondrial DNA exists in the inner matrix and this is in close proximity to the inner membrane where electrons can form unstable compounds, mtDNA has a relatively high chance of getting damaged by ROS. This entails mutations to mtDNA (or straighout deletions of many base-pairs) that can result in the manufacturing of mutant ETC proteins that, in turn, can lead to the leaking of more electrons and more ROS. This so called "vicious cycle" is hypothesized to play a critical role in the aging process according to the mitochondrial theory of aging.
Evidence for Mitochondrial Dysfunction Being Causal in Aging
There is a wealth of evidence that suggests that mitochondria are implicated in aging process and senescence. Specifically, loss of mitochondrial genome integrity is speculated to constitute. When the proofreading component of mitochondrial polymerase was knocked out in mice models, the mtDNA mutations that resulted caused a phenotype resembling premature aging (Larrson et al., 2004). Additionally, mtDNA mutations are found to accumulate with age in humans. Yet, it cannot be said that the mice phenotype literally is aging. It simply resembles aging. Similarly, the acculumation of mtDNA mutations might be the byproduct of a process more fundamental to bringing about aging, rather than actually causing aging. Only more experiments will determine the exact role of mitochondrial in the aging process.
If mitochondria do in fact hold a crucial role in the aging process, then preventing or reversing mitochondrial dysfunction would theoretically attenuate the aging process. A number of experimental methodologies are currently being employed to test this hypothesis.
One such method, termed "allotopic expression" involves the use of gene therapy to introduce copies of mitochondrial genes into the nucleus. This entails the production of proteins normally synthesized in the mitochondrion to be produced in the nucleus, which will subsequently be imported to the mitochondrion and, if all goes well, these proteins will function normally in the mitocohndrion. This process is plagued by a myriad of complications including: 1) protein ratio problems, ie. how to get the transgenic nuclear genes to be expressed in the proper molar ratio; 2) mutant proteins will still be produced, and the import of working proteins might not significantly reduce damage produced due to the remaining mutant proteins; 3) differing genetic code in mitochondria for the translation of codons entails the feasible yet laborious task of changing any differing codons; 4) import/targeting problems with hydrophobic proteins: complex mechanisms exist for importing mitochondrial proteins, and difficult workarounds must be engineered to allow the mitochondrial import of certain hydrophobic proteins; 5) general problems associated with gene therapy will have to be addressed, such as immunological issues with repeated trials and limitations on viral vector size (especially for the putative import of the entire mitochondrial genome).
One promising avenue of research is that of mitochondrial "protofection," or the use mtDNA-protein hybrids to deliver wildtype mitochondrial DNA to mitochondria (Khan and Bennett, 2004). If the mtDNA can be effectively delivered to the mitochondria, expressed, and the effects of mutated mtDNA in turn offset, then the age-associated accumulation of mtDNA mutations could theoretically be phenotypically nullified.
Only more experimentation can elucidate the etiology of cellular aging and mitochondria's role therein. As these are better understood, and if experimental progress with the aforementioned putative therapies proves fruitful in mammilian models, eventually we can put them to the test in human clinical trials and determine if holding back the pollution these engines of energy generate will, in fact, lead to a cellular fountain of youth.
Selected Publications on Mitochondrial and Aging
Also see the Mitochondrial Diseases Page