The new field of “mitochondrial medicine” offers a whole new perspective on the study, diagnosis and treatment of disease.
|David Ellis||Lawrence I. Grossman||Maik Hüttemann||John Kamholz|
Recent breakthroughs in genetics open the door to early and accurate diagnostic tests and to precisely targeted therapies for multiple diseases. Indeed, it is not too much to say that the accelerating pace of discoveries and developments in genetics and molecular medicine promise (or threaten, to the unprepared) to change the nature of health care delivery in the foreseeable future. An emerging key element for understanding human genetics, extending disease diagnosis and providing novel therapies is the mitochondrial component of the cell.
Mitochondria are “organelles”--organs inside the cell; an average cell contains about 4,000 of them. They probably started life as free-living alien organisms with their own DNA (mitochondrial DNA or mtDNA for short) and their own metabolism, but eventually took up residence within the so-called proto-eukaryotic ancestors of our cells, possibly after being ingested as food. Once inside, however, the ingested bacteria became dependent on the cell for nutrients--sugars, fats and proteins--while converting these into energy in the presence of molecular oxygen for its host. These mitochondria thus provide the organism with a very efficient energy production process in an oxygen-containing environment. More than 90 percent of cellular energy (in the form of ATP, the general energy currency in all of our cells) is produced by the mitochondria.
Unfortunately for the organism, mitochondria not only produce energy (and heat, as a byproduct) but also free oxygen radicals, which are toxic to the cell. Free oxygen radicals can damage tissue directly, including DNA, and over the long run contribute to our aging process and eventual death. Damage accumulates over time and leads to impaired energy production and/or increased generation of oxygen radicals. In the short term, however, the acute production or accumulation of free radicals can also overwhelm the cell and contribute to a wide range of age-related disorders, including Parkinson’s disease, ALS and dementia. Various cancers also appear to involve mitochondrial dysfunction. In the end, we die because of energy depletion; radicals just speed up this process.
Spikes in free radicals can occur if the mtDNA mutates, which is relatively frequent given that mtDNA is present in thousands of copies per cell. In comparison, the cell’s own nucleus contains only two copies of native DNA (nuclear DNA or nDNA for short.)
Douglas C. Wallace, director of the Center for Molecular & Mitochondrial Medicine and Genetics at UC Irvine, has postulated that some degenerative diseases may be a result of the interaction of our fast-changing environment--including increased dietary intake of protein and fat--with our metabolic machinery, which has been shaped by evolutionary forces for a diet much lower in these substances. Wallace suggests that some mutations in mtDNA that enabled our forebears to live on a diet low in fats and protein, today, in the presence of higher concentrations of these substances, are deleterious, and lead to the production of high amounts of toxic free oxygen radicals, cellular damage and disease. Energy metabolism and its regulation are thus central to the maintenance of good health, and alterations in energy metabolism are increasingly recognized as contributing to the pathophysiology of disease as well as disease outcomes.
The growing list of relatively common diseases associated with alterations in mitochondrial metabolism includes Alzheimer’s disease, Parkinson’s disease, type II diabetes, multiple sclerosis, stroke and ischemic heart disease. Mitochondrial defects have also been implicated in inherited neuropathies, such as Charcot-Marie-Tooth disease, and motor neuron disease. In addition, a number of diseases have also been identified that are caused by specific mutations in mtDNA. Although these diseases are relatively rare, they are important for helping us understand the role of mitochondria in various tissues, and how alterations in mitochondrial function can lead to tissue injury. For example, Leber’s hereditary optic neuropathy, caused by a single mutation in mtDNA, leads to damage of the optic nerve and blindness. Further understanding of the molecular pathogenesis of this disease could thus lead to better treatments for more common eye disorders, including traumatic injury to the optic nerve.
Following is a summary of mitochondria-related diseases as currently understood:
Traditional mitochondrial diseases--important but relatively rare
- Mitochondrial mutations: LHON (Leber’s hereditary optic neuropathy); MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes); MERRF (myoclonic epilepsy with ragged red fibers); NARP (neuropathy ataxia and retinitis pigmentosa); SNHL (non-syndromic and aminoglycoside-induced sensorineural hearing loss)
- Mitochondrial deletions/rearrangements: KSS (Kearns-Sayre syndrome); Pearson’s Syndrome; PEO (progressive external ophthalmoplegia)
- Nuclear Mutations: A large (and growing) number of diseases that can be attributed to mutations in nuclear genes. Example: Leigh’s Syndrome
Emerging mitochondrial diseases--high impact due to high (and increasing) incidence
- Cancer, e.g., switching from aerobic to glycolytic metabolism
- Neurodegenerative diseases, characterized by impaired mitochondrial energy metabolism
Tests to detect, and therapies to correct, mitochondrial deficiencies are showing increasing promise in controlling or curing the diseases they cause. For example, photobiomodulation therapy using low-energy infrared light (IRL) to increase aerobic energy metabolism has already been shown to accelerate wound healing and to attenuate degeneration of the injured optic nerve. Infrared photons can deeply penetrate tissue and reach nerves under the skin surface or inside the brain. IRL therapy is effective, safe and noninvasive, though there remain gaps in understanding that impede the translation of such research successes into clinical practice.
Closing those gaps requires a deeper understanding of energy metabolism and its regulation, as well as the conduct of and support for population-based research and databases in genomics and health, the development of the evidence base for genomic applications in health promotion and disease prevention, and the assurance of an adequate public health capacity in genomics.
David Ellis is corporate director of planning and future studies at the Detroit Medical Center and publisher of Health Futures Digest, a monthly online discursive digest of news and commentary on long-range, leading-edge technological innovations and their consequences and implications for health care policy and practice. Mr. Ellis is also a regular contributor to H&HN OnLine.
Lawrence I. Grossman, Ph.D., is professor and director of Molecular Medicine and Genetics and professor of internal medicine at Wayne State University in Detroit. Maik Hüttemann, Ph.D., is assistant professor of molecular medicine and genetics and of molecular biology and biochemistry at Wayne State University. John Kamholz, M.D.,Ph.D., is professor of neurology and of molecular medicine and genetics, also at Wayne State University.
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This article first appeared in the on June 27, 2006 in HHN Magazine online site.