Mitochondria Lab Report

Aging affects all living organisms, which is characterized by the loss of cellular homeostasis causing systemic cellular dysfunction. In fact, both the mitochondrion and the actin cytoskeleton show age-associated declines in functions. As an organism age, mitochondria accumulate mtDNA mutations, which result in mitochondrial dysfunction. The actin cytoskeleton also declines with age. This affects establishment and maintenance of cell polarity as well as cellular and intracellular movement, which in turn contributes to age-associated declines in systems including the immune system and skeletal muscle. In addition, many age-related pathologies like neurodegenerative diseases, such as Alzheimer’s, display dysfunction in mitochondria and actin. Interestingly, Dr. Liza Pon’s

lab has established actin cytoskeleton dynamics as a contributor to mitochondrial quality control and asymmetric inheritance of mitochondria during cell division. Specifically, in yeast as in other organisms babies are born young, largely independent of the age of the mother.

The finding that this process, mother-daughter age asymmetry, occurs in yeast, a single cell organism, led to the model that aging determinants may be preferentially retained by mother cells and rejuvenating determinants are preferentially inherited by daughter cells. Our lab has shown that mitochondria are asymmetrically inherited during yeast cell division and that inheritance of fitter mitochondria by yeast daughter cells is dependent upon that actin cytoskeleton and necessary for daughter cells fitness and lifespan. We carried out a genome-wide screen to identify genes, which when deleted reduce the sensitivity of yeast to the growth inhibiting effects on Latrunculin-A (Lat-A), an actin destabilizing drug, treatment. We have identified multiple genes whose deletion exhibited decreased sensitivity to Lat-A, increased number of actin cables (bundles of F-actin that serve as tracks for movement of mitochondria and other cargos from mother cells to buds), increased mitochondria quality, and extended lifespan. One of the genes identified is a previously uncharacterized open reading

frame. Our preliminary evidence indicates that this gene affects nutrient sensing through the Tor1 pathway, a known regulator of mitochondrial biogenesis and lifespan. Emerging evidence also supports Tor1 in control of actin dynamics. We propose to study 1) how mitochondria and actin decline as a function of age in living yeast; 2) whether interventions that promote actin stability or dynamics delay age-associated declines in mitochondrial function and extend lifespan; 3) whether the lifespan extension observed upon deletion of our gene of interest is a consequence of effects on actin or mitochondrial or both; and 4) how the protein regulates nutrient sensing.