MTFR2 regulates mitochondrial fission and impacts spindle integrity during mitosis

Abstract Previously we reported that mitochondrial fission regulator 2 (MTFR2, also termed DUFD1 or FAM54A) is co-transcribed with core centromere/kinetochore components, indicating a possible role in mitosis regulation. Here we show that human MTFR2 is a mitochondrial outer membrane protein and participates in DRP1 dependent mitochondrial fission. Multiple MTFR2 variants identified in cancer samples are defective in triggering mitochondrial fission. Inducible MTFR2 depletion caused prolonged mitotic duration and increased chromosome mis-segregation, resulting in multi-nucleated daughter cells. MTFR2 knockout cells accumulated spindle defects, producing either multipolar spindles or short oscillating spindles due to loss of astral microtubules. MTFR2 is phosphorylated during mitosis. The phosphorylation mutant, as well as the cancer variants, failed to correct the prolonged mitotic duration. MTFR2 knockout also rendered cells more resistant to apoptosis caused by taxol treatment. As overexpressing MFN1 or DRP1-K38A also caused spindle defects, we conclude that mitochondrial fragmentation during mitosis ensures spindle integrity and chromosomal stability, and MTFR2 plays a critical role in bridging proper mitochondrial fission and chromosome segregation.