Regulation of mitochondrial inheritance by Myo19
Final Report Abstract
Mitochondria, the powerhouses of the cell, are limited by an outer smooth membrane and an inner, highly folded membrane. In this inner membrane are embedded the protein complexes of the respiratory chain that produce the cellular fuel ATP. The outer mitochondrial membrane engages in membrane contacts with other organelles. Via such membrane contacts mitochondria exchange lipids and Ca2+-ions with the endoplasmic reticulum. In the matrix surrounded by the inner membrane they have copies of a mitochondrial genome. The mitochondria can fuse with each other and form branched networks or undergo fission and separate into smaller units. At the beginning of mitosis, the mitochondria divide extensively, resulting in many individual mitochondria that are evenly distributed around the spindle. During the subsequent cell division they are disseminated evenly between the daughter cells. We are studying the roles of the actin-based motor molecule myosin-19 (Myo19) that is associated with the outer mitochondrial membrane receptor proteins Miro1 and Miro2. It transmits mechanical force generated along actin filaments to the mitochondria. To investigate the functions of Myo19, we deleted Myo19 expression in cells and mice by genome editing. Changes in mitochondria, cells and mice due to the lack of Myo19 were then examined and the underlying mechanisms were elucidated. The absence of Myo19 led to altered morphology of the inner mitochondrial membrane. Myo19 transmits mechanical force from the outer to the inner membrane via a protein complex that connects the outer and inner membranes and simultaneously forms the junctions of the inner membrane folds. The absence of Myo19 further led to increased levels of reactive oxygen species (ROS), which reduced cell adhesion by impairing focal contacts. Mitochondria’s oxygen consumption rate was also reduced. Furthermore, the absence of Myo19 led to a reduction in the numbers of membrane contacts of the mitochondria with the endoplasmic reticulum. This was accompanied by an altered lipid composition of the mitochondria, which could contribute to the altered morphology and function of the inner membrane. During mitosis, the mitochondria in Myo19-deficient cells were not fragmented because they continued to fuse with each other unabated. They accumulated asymmetrically at the spindle poles and were distributed unevenly among the daughter cells. Cell division was stochastically blocked. Surprisingly, however, mice that were deficient for Myo19 did not show any obvious phenotypes, despite the observed changes in the mitochondria and cells.
Publications
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Coordination of mitochondrial and cellular dynamics by the actin-based motor Myo19. Journal of Cell Science, 134(10).
Majstrowicz, Katarzyna; Honnert, Ulrike; Nikolaus, Petra; Schwarz, Vera; Oeding, Stefanie J.; Hemkemeyer, Sandra A. & Bähler, Martin
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Myosin-19 and Miro Regulate Mitochondria–Endoplasmic Reticulum Contacts and Mitochondria Inner Membrane Architecture. Cells, 14(21), 1657.
Attia, Aya; Majstrowicz, Katarzyna; Shembekar, Samruddhi; Honnert, Ulrike; Nikolaus, Petra; Lohmann, Birgit & Bähler, Martin
