Swe1 delays cell cycle progression during impaired mitochondrial inheritance to promote mitochondrial homeostasis

Abstract

Mitochondrial homeostasis is essential for cellular health. To maintain mitochondrial homeostasis in proliferating cells, mitochondrial inheritance to daughter cells must be tightly coordinated with growth and cell division. In budding yeast, mitochondrial inheritance is ensured by active transport into the growing bud. Although inheritance defects are well known to affect cell physiology, the regulatory mechanisms linking mitochondrial inheritance to cell cycle control remain unclear. Here, we use the inheritance defect of cells depleted of the mitochondrial inheritance adaptor Mmr1 to investigate this coordination. Time-resolved analysis of more than 8,000 budding events revealed that budding duration is directly linked to the time of mitochondrial inheritance. To understand the underlying mechanism, we performed a genetic interaction screen using the auxin-inducible degron library. Strains depleted of cell cycle regulators, particularly those involved in mitotic progression, were highly enriched in clones with synthetic growth defects. Among these, Swe1, the bud morphogenesis checkpoint kinase, emerged as a key candidate affecting budding duration in response to impaired mitochondrial inheritance. Co-depletion of Mmr1 and Swe1 strongly reduces the mitochondrial inheritance-dependent lengthening of budding duration, leading to a large fraction of daughter cells with insufficient mitochondrial content. Thus, Swe1-mediated mitotic delay contributes to slowing cell cycle progression in response to defective mitochondrial inheritance. We suggest calling this regulatory loop MIBA: mitochondrial inheritance-dependent budding adaptation. Together, our findings reveal a mechanism by which cells couple mitochondrial inheritance to cell cycle progression and highlight the importance of this coupling for mitochondrial homeostasis across the population.