Study of myosin-Va role in the processes of mitochondrial dynamics and mitophagy

Abstract

Mitochondrial architecture is involved in several crucial functions for cell viability, as proliferation, senescence and signaling. Mutations that affect these processes are common causes of neurologic, muscular and metabolic disorders and cancer. In particular, the mitochondrial dynamics through the balance between fusion and fission, and the mitophagy to remove damaged mitochondria, play a central mechanism for adjusting the bioenergetic metabolic needs of the cell. The cytoskeleton and molecular motors have been shown to be important in the processes of mitochondrial homeostasis. Myosin-Va, a molecular motor dependent on F-actin, promotes some phenotypes that suggest a possible role in cell metabolism. For example, knockdown of myosin-Va, as well as the DRP1, an essential GTPase for mitochondrial fission, makes more elongated mitochondria with increased cellular respiration rates and ROS production, and is also connected to the decrease of invasiveness, migration and increased apoptosis rates of transformed cells. It was also shown that there is a cellular colocalization of myosin-Va and mitochondria, which led us to hypothesize that myosin-Va is involved in the processes of mitochondrial dynamics, participating in the fission process together with F-actin, which is required in the process, or even placing DRP1 to the fission sites. Furthermore, the AAA-ATPase p97/VCP, which is required for the Parkin dependent mitophagy, binds to myosin-Va. This led us to an alternative hypothesis, that myosin-Va contributes to the mitochondrial homeostasis through the mitophagy process. Therefore, our goal is to elucidate the role of myosin-Va in the processes of mitochondrial dynamics and mitophagy, and thus better understand how the regulation of metabolic processes occurs in cancer cells. (AU)