Parameter Space Search.

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.