2012 Theses Doctoral

Mitochondrial Inheritance and Function in the Lifespan Control of Budding Yeast

McFaline Figueroa, Jose Ricardo

Mitochondria are essential organelles that cannot be synthesized de novo and must be inherited by daughter cells. During cell division, mitochondria align along the mother- daughter axis of the dividing cell, exhibit bidirectional poleward movement and are anchored at the cell poles. Mitochondria anchored at the bud tip and thus destined to be inherited by the daughter cell, show markers of increased fitness, lower superoxide burden and less oxidizing mitochondria, while less fit mitochondria are retained in the mother. In this work, the mechanism for anchorage of fit mitochondria to the bud tip and its effect on yeast lifespan determination are presented. Mitochondria at the bud tip are associated with cortical ER (cER) sheets underlying the plasma membrane. Mmr1p, a member of the DSL1 family of tethering proteins, mediates anchorage of mitochondria at the bud tip by binding to both mitochondria and cER at this site. A conserved protein phosphatase, Ptc1p, regulates mitochondrial anchorage by dephosphorylation of Mmr1p.

Mitochondrial fitness decreases as a function of age, yet retention of less fit mitochondria occurs to the same extent in young and older cells. Disruption of mitochondrial anchorage at the bud tip by deletion of MMR1 results in a severe lifespan anomaly, such that some cells have drastically reduced lifespan and markers of aged cells, while others show increased lifespan and markers of young cells. Loss of anchorage also leads to defects in mitochondrial quality control during inheritance and mitochondrial fitness correlates to the aging phenotypes observed in mmr1-delta cells. These findings support the model that the mitochondrial inheritance machinery promotes retention of lower-functioning mitochondria in mother cells and that this process contributes to both mother- daughter age asymmetry and age-associated declines in cellular fitness.