Mitochondria (MT) are organelles commonly referred to as the powerhouse of the cell due to the fact that their main function is to generate ATP to provide energy for cellular functions. Mutations that cause DNA instability often lead to a wide range of MT diseases, which was the topic of the "Mitochondria As the Central Target of Environmental Contaminants, Pharmaceutical Agents, and Toxicants: Mechanisms of Toxicity and Disease" session.
Developing therapies for MT disorders poses a great challenge due to the fact that MT are susceptible to mutations from environmental, lifestyle, and genetic factors. Also, unlike other genes where there are two copies per cell, one from each parent, only a single maternal copy of the MT gene is present. To make matters worse, MT lack a robust DNA checkpoint and repair mechanisms to correct for mutations.
Because MT are present in all cells, defects can affect multiple tissues and cause a wide range of disorders from cancer to Parkinson's. Recent findings presented during this session have identified manganese-dependent superoxide dismutase (MnSOD) as a master regulator in redox signaling in MT, which when overexpressed leads to reduced respiration. Increased levels of MnSOD also were correlated with cancer progression. Regulation of MnSOD resulting in production of hydrogen peroxide and downstream signaling by the transcription factor hypoxia inducible factor 2 alpha (HIF-2A) appear to play a critical role on tumorgenesis and may be a target for future therapies.
Studies in alternative animal models such as zebrafish and C. elegans also are revealing clues for therapeutic targets. Both homozygous and heterogeneous DNA polymerase gamma (Pol g), the only replicative DNA polymerase in vertebrate MT, were found to cause developmental defects that adversely affect the central nervous system (CNS) without impairing MT function or respiration rate, highlighting the importance of identifying defects associated with specific mutations prior to developing therapeutics. C. elegans studies suggest that developmental stage, genetic background, and metabolism are all important factors to consider in MT disorders.
Although we are still far from reaching the goal of improving MT disease pathologies, studies using different model systems to assess toxicology of MT disorders are certainly paving the way to therapeutic development in the near future. It is estimated that 20 percent of healthy humans carry potentially pathogenic MT DNA mutations and would benefit from any treatment developed.