Biased placement of Mitochondria fission facilitates asymmetric inheritance of protein aggregates during yeast cell division

Mitochondria are essential and dynamic eukaryotic organelles that must be inherited during cell division. In yeast, mitochondria are inherited asymmetrically based on quality, which is thought to be vital for maintaining a rejuvenated cell population; however, the mechanisms underlying mitochondrial remodeling and segregation during this process are not understood. We used high spatiotemporal imaging to quantify the key aspects of mitochondrial dynamics, including motility, fission, and fusion characteristics, upon aggregation of misfolded proteins in the mitochondrial matrix. Using these measured parameters, we developed an agent-based stochastic model of dynamics of mitochondrial inheritance. Our model predicts that biased mitochondrial fission near the protein aggregates facilitates the clustering of protein aggregates in the mitochondrial matrix, and this process underlies asymmetric mitochondria inheritance. These predictions are supported by live-cell imaging experiments where mitochondrial fission was perturbed. Our findings therefore uncover an unexpected role of mitochondrial dynamics in asymmetric mitochondrial inheritance. In this study, we sought to unravel the complex process of how cells segregate damaged parts of mitochondria, ensuring the healthier mitochondria to be passed on to progeny cells. Using budding yeast as a model organism, we characterized how the presence of misfolded protein aggregates in mitochondrial matrix alters mitochondria remodeling dynamics, leading to an asymmetric retention of these protein aggregates in the aging mother cell. Through a combination of stochastic agent-based modeling and high spatiotemporal microscopy imaging, we found that aggregated misfolded proteins inside mitochondria cause mitochondria to fission unevenly. This skewed division, or "biased fission", promotes the clustering of aggregates, which facilitates their retention by the mother cells. By genetically perturbing key components of fission machinery, we show that impaired mitochondrial fission reduces the rate of aggregate clustering and elevates their propagation into the daughter cell.