Mitochondrial function and protein homeostasis are key contributors to the aging process and the onset of age- associated diseases. This proposal describes plans to examine mitochondrial protein folding and function in the context of C. elegans development and aging to further elucidate the molecular mechanisms cells employ to protect organelle function. Mitochondria are dynamic organelles, which are remodeled during diverse conditions including nutrient deprivation and cellular differentiation. Mitochondrial metabolic output has long been appreciated as a contributor to the aging process, primarily through the detrimental effects of reactive oxygen species generated by the electron transport chain. Additionally, mutations in the mitochondrial genome accumulate over time due to errors introduced during DNA replication. Both forms of damage challenge the already complex protein-folding environment in the organelle. To function properly during organelle remodeling and stress, the mitochondrial protein-folding environment must be maintained by molecular chaperones and proteases. We have identified a mitochondrial unfolded protein response, a signaling pathway that adjusts the organelle's folding capacity to the load of unfolded proteins that accumulate during stress by regulating the expression of mitochondrial chaperone genes. And, more recently we have discovered a requirement for a complementary translation regulation pathway. Consistent with a role in organelle protection, animals lacking components of either pathway are sensitive to conditions that perturb mitochondrial function. Here, we describe plans to further elucidate the mechanism of signal transduction within each pathway as well as their impact on development, aging and age-associated damage. Additionally, we plan to uncouple activation of each stress response pathway from mitochondrial biogenesis or stress to expand organelle folding capacity and determine the impact on lifespan and resistance to proteotoxicity.
Mitochondrial dysfunction is prevalent in diseases ranging from Parkinson's and Friedreich's ataxia to cancer. Cells respond to mitochondrial insults but the stress responses are eventually overwhelmed leading to the disease state. A thorough understanding of the molecular pathways cells employ to protect against mitochondrial dysfunction will allow for the development of therapeutic manipulations potentially able to limit age or disease-associated mitochondrial damage.
|Pellegrino, Mark W; Nargund, Amrita M; Kirienko, Natalia V et al. (2014) Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature 516:414-7|
|Haynes, Cole M; Fiorese, Christopher J; Lin, Yi-Fan (2013) Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded-protein response and beyond. Trends Cell Biol 23:311-8|