Environmental Factor, October 2011, National Institute of Environmental Health Sciences
Meyer returns to NIEHS to discuss mitochondrial DNA damage
By Jeffrey Stumpf
Meyer answered a question about possible epigenetic responses to mitochondrial DNA damage. His interest in mitochondria dates back to the end of his graduate work that led to superfund research. (Photo courtesy of Steve McCaw)
NIEHS Program Analyst Astrid Haugen introduced her former colleague in the LMG. (Photo courtesy of Steve McCaw)
As chief of the LMG and head of the Mitochondrial DNA Replication Group, William Copeland was clearly interested in Meyer's findings about mtDNA and mitochondrial disease. (Photo courtesy of Steve McCaw)
Kasiviswanathan, a postdoctoral fellow in the Mitochondrial DNA Replication Group, collaborated with Meyer's group to determine the mutagenic potential of UV-induced mtDNA damage. (Photo courtesy of Steve McCaw)
It was a homecoming of sorts for Duke University Nicholas School of the Environment Assistant Professor and NIEHS Outstanding New Environmental Scientist (ONES) awardee Joel Meyer, Ph.D.(http://fds.duke.edu/db/Nicholas/esp/faculty/jnm4) , who presented a lecture at NIEHS Sept. 21. The former Laboratory of Molecular Genetics postdoctoral fellow summarized his research on the effects of mitochondrial DNA damage caused by environmental agents, work he began during his training at NIEHS.
As cellular power plants, mitochondria produce the majority of the energy storage molecule ATP. Mitochondria also contain a small genome, separate from nuclear DNA, that encodes 13 proteins necessary for ATP production. Because the mitochondrial genome (mtDNA) is essential for healthy cells, mtDNA mutations are associated with mitochondrial diseases, Parkinsonism and Alzheimer's disease, aging, and cancer.
Mitochondria as the canary in the cell
MtDNA is as much as 50- to 500-fold more sensitive to environmental damaging agents than nuclear DNA, providing a direct impact on human health. For instance, many potential pharmaceutical agents have been rejected because of intolerable side effects due to mitochondrial damage.
“Screening for mitochondrial toxicities is something drug companies spend a lot of time studying,” Meyer explained. The economic consequences of failure so far into the process of drug development can be disastrous.
Pollutants such as polycyclic aromatic hydrocarbons, commonly called PAHs, food contaminants such as mycotoxins, and environmental damaging agents such as UV sunlight are also harmful to mitochondria. Meyer insists that mitochondrial damage caused by environmental agents deserves much more attention than it has received.
“Most pollutants are much less studied than almost any pharmaceutical, and yet it took decades to determine that some pharmaceuticals are mitochondrial toxins,” Meyer remarked.
What do cells do with damaged mitochondria?
While nuclear DNA has an array of repair mechanisms, UV-damaged nucleotides in mtDNA are not repaired. One possible outcome is that mtDNA replication proceeds through the damage. Meyer presented data from collaborations with NIEHS researchers William Copeland, Ph.D., and Rajesh Kasiviswanathan, Ph.D., demonstrating that replication past mtDNA damage causes insertion of incorrect nucleotides which could cause mutations. Because mtDNA is inherited only maternally, Meyer considered the consequences of a mutagenic effect of mtDNA damage that could linger through generations.
“What's frightening from a human health perspective is that you might have to think about the grandmother's exposure to environmental agents,” Meyer postulated.
There are hundreds of mitochondria and thousands of mtDNA molecules per cell, implying that infrequent mtDNA damage is inconsequential. To study the fate of damaged mtDNA, Meyer tested the effects of UV light on the roundworm Caenorhabditis elegans, whose life cycle makes it an ideal model organism. Copy number of mtDNA follows a bottleneck pattern, where mtDNA is most prevalent in the mature oocyte but drops precipitously during the first larval stage (L1) as cell division occurs without mtDNA replication. MtDNA copy number increases during the subsequent larval stages, returning to the high copy number in the next oocyte.
Transition from the third to fourth larval (L3 to L4) stage requires functional mitochondria. Meyer's research group applied UV damage at the first larval stage (L1) of worms that were deficient in several pathways involved in mitochondrial maintenance and counted those that survived to L4.
Meyer definitively demonstrated that worms unable to fuse mitochondria died of mitochondrial defects after UV exposure. This result suggests that a typical response to persistent mtDNA damage involves joining mitochondria with undamaged mtDNA and targeting damaged mitochondria for degradation. Interestingly, mutations in the human mitochondrial fusion gene OPA1 are associated with mitochondrial disease, and environmental exposures could exacerbate the disease state.
“It gets back to the NIEHS paradigm,” Meyer explained. “There are genetic effects that are associated with mitochondrial related diseases and [environmental] exposures causing persistent mtDNA damage. The interaction of those two in the context of when the exposure occurred will be most important.”
(Jeffrey Stumpf, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Mitochondrial DNA Replication Group.)
Expanding research into gene-environment interactions
Meyer has received NIEHS support(https://projectreporter.nih.gov/project_info_description.cfm?aid=8182618&icde=0) for his long-term career commitment to research in areas of environmental health and problems of environmental exposures and disease. NIEHS Division of Extramural Research and Training Program Administrator, Cindy Lawler, Ph.D., believes that Meyer's research is well focused on the mission of NIEHS.
“Joel will bring his expertise in mtDNA damage and repair pathways, together with a tractable model system, to address a novel gene-environment interaction hypothesis in Parkinson's disease,” commented Lawler. “The knowledge gained in his studies may help to identify susceptible populations for targeted prevention efforts and suggest new avenues for intervention.”