Regulation of mitochondrial inheritance by Myo19

• Applicant: Professor Dr. Martin Bähler
• Subject Area: Cell Biology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419818378

Mitochondria contain their own DNA and cannot form de novo. This implies that at cell division mitochondria have to coordinate their inheritance during partitioning to daughter cells. They are highly dynamic and undergo fusion and fission in a cell cycle dependent manner. Blocking fission or increasing fusion leads to stochastic failure of cytokinesis. Inappropriate movement and distribution of mitochondria during mitosis blocks their faithful segregation during division. Both too low and too high mitochondria content have been associated with various cellular deficits and the development of pathogenesis. In mammalian cells mitochondrial transport is predominately microtubule-based. The motor proteins kinesin and dynein associate with the help of the adaptor protein TRAK to the outer mitochondrial membrane protein Miro, a RhoGTPase and direct bidirectional movement along microtubules. Additionally, one finds also actin-based motor proteins associated with mitochondria such as myosin XIX (Myo19). Myo19 competes with the adaptor protein TRAK for binding to Miro and this binding stabilizes the Myo19 protein. Knockdown and overexpression of Myo19 both cause a redistribution of mitochondria to the perinuclear region. These results suggest that Miro coordinates microtubule- and actin-based mitochondria movement. In cells that lack Myo19 mitochondria segregate during mitosis asymmetrically to the spindle poles and are partitioned unequally to daughter cells. In addition, Myo19-deficient cells demonstrate a stochastic failure of cytokinesis. How Myo19 regulates mitochondria segregation and cytokinesis and what the physiological consequences are of asymmetric mitochondrial inheritance, is currently not well understood. We propose to unravel the molecular mechanisms by which Myo19 regulates mitotic segregation of mitochondria using a broad spectrum of state of the art cell biological methods. Furthermore, we propose to study how cells cope with an altered content of mitochondria. For that purpose Myo19-deficient cells will be sorted according to mitochondrial content followed by analysis of various functional and metabolic parameters.

• DFG Programme: Research Grants