This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this research protocol is to continue my thirty year investigation of the nature and prevalence of mitochondrial disease. The mitochondria are organelles within the cytoplasm of our cells that produce most of the energy necessary for cellular function. The mitochondrial are in fact semi-autonomous bacteria living within our cells. These bacteria interred the progenitors of our cells as symbionts about three billion years ago, before multi-cellular plants and animals evolved. Today these mitochondria are an integral part of our cells without which we could not live. Each cell contains hundreds of mitochondria, each of which produces a portion of the energy that the cell requires. Thus, if too many mitochondria become damaged, the cell experiences the equivalent of a metropolitan brown-out resulting from the malfunction of multiple electrical power plants. In the human body, the systems most reliant on mitochondrial energy production are the brain, heart, skeletal muscle, kidney, liver, and endocrine tissues. Since cells with defective mitochondria will malfunction, they would compromise the function of the surrounding tissue. Thus, cells with defective mitochondria must be eliminated. This is accomplished through a self-destruct switch built into the mitochondrion, the mitochondrial permeability transition pore (mtPTP). When mitochondrial energy metabolism declines too much and/or oxidative damage becomes too great, then the switch is thrown and the defective mitochonidria and surrounding cell are destroyed by programmed cell death (apoptosis). While this process removes the offending cell, eventually too many cells are lost. Then the tissue and organ can no longer do their job and disease symptoms insue. Our Center was the first to prove that defects in energy metabolism can cause disease. This was accomplished by identifying the first pathogenic mtDNA mutation which altered an mtDNA-encoded protein. This ND4 polypeptide mutation at np 11778 causes a form of blindness known as Leber's Hereditary Optic Neuropathy (LHON). Most LHON families harbor a homoplasmic mtDNA mutation. The next mutation we discovered altered the mtDNA tRNALys gene at np 8344 and causes the multi-system 'MERRF Syndrome (Myoclonic Epilepsy and Ragged Red Muscle Fibers). This mutation is always heteroplasmidc, and consequently the symptoms associated with the mutation varied dramatically between maternal relatives. Some individuals have no discernable symptoms, others only mild muscle weakness and/or deafness, while the most severely affected individuals experience devastating multi-system disease including dementia, cardiovascular disease, epilepsy, weakness, deafness, renal dysfunction, etc. Since these discoveries in the late 1980s, many more mitochondrial diseases have been identified. Over 150 pathogenic mtDNA base substitution mutations have been identified and hundreds of mtDNA rearrangements have been mapped. Examples of some of the symptoms that have already been linked to mitochondrial disorders include blindness, deafness, movement disorders, dementia, epilepsy, strokes, cardiomyopathy, progressive muscle weakness, vomiting and intestinal dysmotility, renal dysfunction, organic acidemia and aciduria, short stature, diabetes mellitus, neonatal hemochromatosis, and a variety of forms of cancer. However, it is likely that this is only a small proportion of the mitochondrial disease that exists in the human population. Because of the systemic importance of the mitochondria and the variability in the phenotypes seen for each mutation, it is clear that no one set of diagnostic criteria can currently define mitochondrial disease. Indeed, much of disease that currently is viewed as idopathy (due to unknown causes) may eventually be shown to be caused by mitochondrial defects. Hence, it has almost become standard for many clinical geneticists to rule out all known forms of hereditary disease, and then refer all of the remaining complex cases to my Center for a mitochondrial evaluation. This is being expanded even further since there is growing evidence that mitochondrial dysfunction plays a role in a number of common clinical enigmatic diseases, including Alzheimer's and Parkinson's disease, cancer and even aging itself. Therefore, there is still a great deal of exploratory research that needs to be done to define the role of mitochondrial defects in disease. Because Mitochondrial Medicine is a new field, our program always straddles the interface between the current 'standard-of-care' and 'research.' Indeed, large numbers of patients are referred to us for a mitochondrial evaluation to determine if they may be the result of a mitochondrial defect. To evaluate such patients, we need to proceed through a series of steps progressing from the known, and thus diagnostic, through to the unknown and thus research. However, since each patient presents differently and there are undoubtedly very large numbers of pathogenic mutations in the mtDNA and nDNA mitochondrial genes that have not been identified but give similar clinical presentation, it will be many years before the full range of mitochondrial diseases have been defined at the molecular level. The importance of understanding these diseases cannot be overstressed, as many patients with mitochondrial defects suffer from complex problems and most never obtain a meaningful diagnosis. Furthermore, there is no effective therapy for atients suffering from a mitochondrial disease, primarily because the disease remains ill defined and misunderstood. Without a program like ours, we will never be able to define the nature and prevalence of mitochondrial disease, determine the biochemical and molecular causes, or create definitive diagnostic tests or effective therapeutics. Therefore, it is the goal of this research protocol to continue my thirty year quest to delineate the nature and prevalence of human mitochondrial disease. To accomplish this objective, we are pursuing four specific aims for this study: (SA1) To define the range of presentations of human mitochondrial diseases; (SA2) to determine the mitochondrial physiological and biochemical alterations associated with different mitochondrial disease presentations; (SA3) to determine the molecular causes of mitochondrial diseases including the mtDNA and nDNA genes affected and the nature of the mutations that occur; and (SA4) to provide accurate and meaningful conclusion to patients, families, and physicians as to the cause of their disease.
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