A Novel Role for Mitochondrial Dysfunction in Mitochondrial Signaling

The applicant's career goal is to become an independent scientist in the field of aging. A comprehensive mentoring plan has been developed to ensure her career development. This research project will address a potential mechanism underlying the paradoxical relationship discovered in C. elegans whereby some mitochondrial electron transport chain (ETC) mutations are associated with increased longevity. One potential mechanism by which mitochondrial dysfunction could contribute to increased longevity is through up- regulation of mitochondrial stress response pathways, such as the mitochondrial unfolded protein response (mtUPR) and increased mitochondrial biogenesis. Indeed, lifespan extension in C. elegans in response to Complex IV inhibition requires up-regulation of the mtUPR. In addition, the inhibition of Complex IV restricted to neuronal tissue can induce the mtUPR in a heterologous tissue, the intestine. This is a key finding that suggests mitochondrial changes in one tissue can send an extracellular signal to distal tissues to induce mitochondrial stress responses and potentially improve mitochondrial and cellular function. However, it is unknown if this mechanism is conserved in mammals. My proposed studies will address this gap in knowledge by utilizing a mouse model of reduced ETC function, Surf1-/- mice. Mice lacking SURF1, an ETC Complex IV assembly factor, have significantly reduced Complex IV activity and have previously been shown to have a greater than 20% increase in median lifespan. Our laboratory has shown that the Surf1-/- mice exhibit an up- regulation in the mtUPR and mitochondrial biogenesis in several tissues and resistance to mitochondrial stressors. The goal of the current study is to test the hypothesis that Complex IV deficiency in Surf1-/- mice wil result in the release of a signaling factor (mitokine) that will induce mitochondrial stress responses (mtUPR and mitochondrial biogenesis) and increase stress resistance in cells from heterologous tissues. To test this hypothesis directly, I will ask whether the mtUPR and mitochondrial biogenesis are induced in wild-type cells in response to conditioned media (CM) collected from cells of Surf1-/- mice. I will also determine whether cellular resistance to mitochondrial stressors in vitro is altered in response to CM collected from cells of Surf1-/- mice Finally, I will determine the identity of the putative mitokine(s) released in response to complex IV deficiency. My preliminary data show that conditioned media from Surf1-/- fibroblasts can induce expression of Lon and Hsp60, components of the mtUPR, in wild-type fibroblasts, supporting my hypothesis. These studies will provide training in molecular biology, mass spectrometry, animal models, and cell culture. These studies are significant because they are the first to investigate the novel mechanisms by which changes in mitochondrial function can release an extracellular signal to induce mitochondrial stress responses in other tissues. The outcome of these studies will have a significant impact in our understanding of the role of mitochondria in aging. PUBLIC HEALTH RELEVANCE: Mitochondrial mutations in invertebrates and mice show an unexpected increase in lifespan in response to mitochondrial dysfunction. This proposal uses a mouse mitochondrial mutant with increased longevity to examine a novel mechanism by which reduced mitochondrial function can contribute to mitochondrial stress signaling pathways and positively impact longevity. As a result, these studies have the potential to reveal exciting new mechanisms by which mitochondria can influence aging in mammals.