MTFR2 in the control of mitochondrial dynamics and mitotic spindle integrity

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PROJECT SUMMARY The PI’s lab has long-term interest in how aberrant mitosis occurs and its relationship to cancer cell heterogeneity. Our prior work has contributed to current understanding about the spindle assembly checkpoint, a critical mechanism to prevent chromosomal instability. Many other factors also help control the fidelity of chromosome segregation. Most relevant to this proposal, there was some evidence indicating that defects in mitochondrial dynamics affect chromosome segregation, but detailed mechanistic analysis is still lacking. Mitochondrial Fission Regulator 2 (MTFR2, also named FAM54A or DUFD1) was retrieved as a gene co-transcribed with key centromere/kinetochore components in our previous study. Such association suggested a role of MTFR2 in mitosis. However, despite the name, not much is known about the biological function or regulation of MTFR2 at the cellular level. Our preliminary results demonstrated that MTFR2 regulates mitochondrial fission in a Drp1- dependent manner. We also found that many cancer-occurring MTFR2 variants are defective in triggering mitochondrial fission. In addition, conditional MTFR2 knockout by inducible Cas9/CRISPR resulted in loss of astral microtubules and multipolar spindles during mitosis, resulting in chromosome missegregation. Building upon the preliminary data, we hypothesize that MTFR2 plays critical roles in coordinating mitochondrial fission and chromosome segregation during mitosis. The overall objective of this project is to further clarify the MTFR2 activity in mitochondrial fission and mitotic progression, and conversely how cell cycle machinery regulates MTFR2 activity. Aim 1 experiments will elucidate the activities and mechanisms of MTFR2 in mitochondrial fission especially during mitosis, and Aim 2 experiments will investigate how compromising MTFR2 activity in mitosis affects chromosome missegregation and taxol resistance. The proposal is expected to expand our understanding about mitochondrial fission mechanisms, and provide insights how mitochondria and chromosome inheritance are coordinated during mitosis to ensure healthy daughter cells. The collaborative project will provide an invaluable platform at the University of Toledo to support and train undergraduate students for hands-on research experience.