Mitochondrial inheritance and quality control

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Asymmetric cell division, the process whereby asymmetric inheritance of cellular components gives rise to two daughter cells that have different characteristics and fates, is essential for development. It is also essential for maintaining stem and progenitor cells, which are critical for tissue and organ renewal and for the lifespan of the organism. We use the budding yeast, Saccharomyces cerevisiae, to study asymmetric cell division and the role of that process in lifespan control. One consequence of asymmetric cell division in S. cerevisiae is mother- daughter age asymmetry, the phenomenon whereby daughter cells or buds are born young, largely independent of the age of their mother cells. We find that mitochondria, established aging determinants, are asymmetrically inherited during yeast cell division. Yeast daughter cells inherit higher-functioning mitochondria, which are more reduced, have higher membrane potential and contain lower levels of reactive oxygen species. We find that the membrane-cytoskeleton interactions that drive mitochondrial movement in budding yeast result in preferential transport of higher-functioning mitochondria from mother to daughter cell. Moreover, we identified components of the tethering machineries that anchor and retain higher-functioning mitochondria in mother and daughter cells. Interestingly, we find that the tether for fitter mitochondria in mother cells responds to previously unappreciated polarity cues and identified a role for the actin cytoskeleton in region-specific localization of the anchor and/or polarity cues. Equally important, we find that promoting inheritance of fitter mitochondria by yeast daughter cells can extend lifespan and promote healthspan (quality of life in advanced age). We will study 1) the polarity cues, its regulators, and new components of the anchorage machinery, 2) the mechanism underlying cytoskeleton-dependent localization of the polarity factor or its regulators to mitochondrial anchorage sites, and 3) the role of the polarity factor, its regulators, and its targets in lifespan control. In complementary studies, we identified a major role for the mitochondria-associated degradation pathway (MAD) in mitochondrial quality control in response to mild oxidative stress in the organelle. MAD is poorly understood. However, it is similar to ERAD, a pathway that recognizes unfolded ER proteins and retrotranslocates them to the surface of the organelle, where they are ubiquitinated and degraded by the proteasome. We will study 1) MAD targets and components within mitochondria, 2) the mechanism of action of MAD components, and 3) the role of MAD in mitochondrial quality control and lifespan control. Although asymmetric inheritance has been studied almost exclusively during development, recent evidence indicates that mitochondria are asymmetrically inherited in human mammary stem-like cells and that this process affects cell fate. Moreover, deletion of a MAD component results in fatal mitochondrial disease in humans. Thus, our studies will provide a foundation for understanding mitochondrial quality control processes in other cell types and potential targets that can promote human health and lifespan.