Investigating the Mechanisms of Mmr1 in Mitochondrial and mtDNA Inheritance

Chen, WeiTing

doi:https://doi.org/10.21985/n2-mdwn-re16

Work

Investigating the Mechanisms of Mmr1 in Mitochondrial and mtDNA Inheritance

Public

Download PDF

Download All Files (.zip)

Proper partitioning of mitochondria and mtDNA is critical for cellular health. Investigations into mitochondrial inheritance, specifically how mtDNA inheritance is coupled with the inheritance mitochondrial compartment, are still in the early stages. We use budding yeast as a model polarized cell system to study a mitochondrial Myo2-adaptor protein, Mmr1, in order to understand the mechanisms by which cells partition mitochondria prior to cell division. Mitochondrial transport and anchoring mechanisms work in concert to position mitochondria and ensure proper mitochondrial inheritance. In budding yeast, Mmr1 functions as a mitochondrial adaptor for Myo2 to facilitate actin-based transport of mitochondria to the bud. Post-transport, Mmr1 is proposed to anchor mitochondria at the bud tip. More importantly, Mmr1 has been suggested to be involved in the asymmetric partitioning of functioning mitochondria and the age asymmetry of budding yeast. Despite its importance, the molecular basis and mechanism of Mmr1-dependent mitochondrial inheritance is poorly understood. Our in vitro phospholipid binding assays indicate Mmr1 can directly interact with phospholipid membranes. Through structure-function studies we identified an unpredicted membrane-binding domain composed of amino acids 76-195 that is both necessary and sufficient for Mmr1 to interact with mitochondria in vivo and liposomes in vitro. In addition, our structure-function analyses indicate that the coiled-coil domain of Mmr1 is necessary and sufficient for Mmr1 self-interaction and facilitates the polarized localization of the protein. Disrupting either the Mmr1-membrane interaction or Mmr1 self-interaction leads to defects in mitochondrial inheritance. Therefore, direct membrane binding and self-interaction are necessary for Mmr1 function in mitochondrial inheritance and are utilized as a means to spatially and temporally regulate mitochondrial positioning. In addition to its role in the inheritance of the mitochondrial compartment, we find that Mmr1 plays a role in maintaining mtDNA integrity over generations and this role for Mmr1 is likely linked to its role in mitochondrial transport. Overall, these findings expand our knowledge of mitochondrial and mtDNA inheritance and contribute to the understanding of mitochondrial partitioning in asymmetrically dividing cells.

Creator