DESCRIPTION (provided by applicant): Mitochondrial oxidative phosphorylation provides the major means of energy production in most eucaryotes. complete removal of this capacity often results in premature death. Recent studies using the nematode Caenorhabditis elegans are surprising because they have revealed that disruption of many of the key components of the normal mitochondria! energy-generating machinery do not result in immediate death, rather they typically result in greater than a 30% increase in adult lifespan. Understanding why these so called Mit (Mitochondrial) mutants are long-lived forms the basis of this proposal. We will test the hypothesis that the Mit mutants are long-lived because their crippled mitochondria are maintained and operated under] conditions that lead to a reduction in their reactive oxygen species (ROS) output. C. elegans is naturally a soil dwelling organism. There are times when it is forced to live under low oxygen conditions. As a consequence it has retained several non-oxygen requiring pathways for the generation of ATP and NAD(P)H. Our current data indicates that use of such alternate pathways is one strategy, that the Mit mutants use to supplement their mitochondria! energy deficit. In this study we will also explore the repertoire of alternate energy production pathways used by Mit mutants. We hypothesize that the products generated by these alternate energy production pathways directly interact with Mit mutant mitochondria to affect their operational parameters, including ROS output. The evolutionary history of C. elegans has permitted this species to retain several pathways for making energy in the presence or low or no oxygen. Humans, on the other hand, have retained only some of these. Nonetheless we believe both species have at their disposal the same basic techniques to potentially lower mitochondria! ROS production. Studying Mit mutants can therefore provide us with an understanding of what new operational settings mitochondria must be set at in order to gain life-span extension. It is conceivable that similar settings may also work for our own cells.
|Effective start/end date||6/1/06 → 5/31/09|
- National Institutes of Health: $169,207.00
- National Institutes of Health: $68,365.00
- National Institutes of Health: $79,932.00