Environmental Factor, June 2010, National Institute of Environmental Health Sciences
New Insights into the Mysteries of Mitochondrial Disease
By Eddy Ball
Researchers in the NIEHS Mitochondrial DNA Replication Group report new findings on mitochondrial DNA (mtDNA) mutagenesis and depletion in the journal Human Molecular Genetics. On the cover of its June 1 issue, the journal features a computer-generated crystal structure image used in the study.
The study (https://www.ncbi.nlm.nih.gov/pubmed/20185557) advances understanding of mtDNA maintenance and points to potential strategies for predicting onset and intervening in the progression of the devastating diseases of the mitochondria. According to the study's principal investigator, Bill Copeland, Ph.D., mitochondrial diseases remain one of the least understood and most intractable to treatment of all human disease.
Characterized by defects in energy production and related metabolic processes in the nervous system and organs of the body, "inherited mitochondrial diseases have a mortality rate roughly that of cancer, with very high rates of premature death," Copeland explained. Copeland is among several experts who speculate that inherited and induced mitochondrial defects may also contribute to the common diseases of aging, such as type 2 diabetes, Parkinson's disease, stroke, and Alzheimer's disease.
Budding yeast offers clues to human mtDNA
Mip1, the mitochondrial DNA polymerase in the budding yeast Saccharomyces cerevisiae, is 43 percent identical to the human mitochondrial polymerase gamma, pol gamma. In their study, the researchers surveyed 31 mutations in MIP1 that were identical to mutations found in mitochondrial disease patients and identified many with mtDNA defects in vivo. According to the researchers, of the 16 known human polymerases, only the POLG-encoded pol gamma is known to replicate DNA in the mitochondria.
The research team characterized five sporadic mutations for the first time. Importantly, the scientists showed that increasing nucleotide pools by overexpressing ribonucleotide reductase (RNR1) suppressed mtDNA replication defects caused by several dominant mip1 mutations.
Discovering potential interventions
The team's experiments determined that the severity of reduced or depleted mip1 correlated with the age of onset of disease associated with defects in pol gamma, suggesting that targeted genetic testing might help clinicians in the future to identify disease in the early stages of development.
The researchers also speculated that overexpressing RNR1 increases mtDNA replication without triggering additional mutations. Thus, targeting RNR1 directly or indirectly could prove to be beneficial for patients by preventing onset or delaying progress of disease.
Copeland explains that by elucidating the mechanisms that promote mtDNA defects, researchers may ultimately discover clues to the role of environmental agents in causing genome instability de novo and among those individuals with genetic susceptibility, potentially informing primary prevention efforts to improve public health.
Support from NIH, NIEHS intramural program, and Summers of Discovery Program
Funding from the NIH, NIEHS intramural program, and NIEHS Summers of Discovery Program supported researchers in this latest study. In addition to Copeland, the team included the first author, NIEHS Postdoctoral Fellow Jeffrey Strumpf, Ph.D., of the Copeland lab, and Summers of Discovery students Diana Spell and Matthew Stillwagon. The NIEHS team collaborated with two investigators in the Anderson Lab (http://info.med.yale.edu/pharm/anderson/index_files/Page327.htm) at the Yale University School of Medicine - Principal Investigator Karen Anderson, Ph.D., and graduate student Christopher Bailey, who were supported by funding from NIH.
Citation: Stumpf JD, Bailey CM, Spell D, Stillwagon M, Anderson KS, Copeland WC. (https://www.ncbi.nlm.nih.gov/pubmed/20185557) 2010. mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae. Hum Mol Genet. 2010 Jun 1;19(11):2123-33. Epub 2010 Feb 25.