Regulation of Mitochondrial Distribution and Inheritance During Cell Division

Abstract

Mitochondria are crucial to the cell and perform numerous functions including generating cellular ATP, buffering calcium, and creating macromolecules. Mitochondria contain their own DNA and as such, cannot be synthesized de novo. Additionally, both nuclear-encoded and mitochondrial-encoded proteins work in concert in order for mitochondria to function. During cell division, the cell goes through dramatic morphological changes to ensure the appropriate amount of DNA is inherited into daughter cells. Given the importance of mitochondria, our study sought to understand the underlying mechanisms that ensure proper mitochondrial inheritance. Organelles are inherited by two mechanisms: active and passive. Through our studies we found that mitochondria go through phases of both active and passive regulation. Initially, mitochondria undergo a release from microtubules, actin, and the endoplasmic reticulum, which allows mitochondria to passively float throughout the cytoplasm. As the cell enters cytokinesis, an active phase occurs that can compensate for some, but not all, asymmetry prior to cytokinesis. The detachment from microtubules, actin, and ER is regulated during cell division, and we discovered the mechanism behind mitochondrial release from microtubules. Dynein and kinesin motors move mitochondria along microtubules and also attach them to the cytoskeleton. During mitosis, motors shed from the mitochondrial surface, thus releasing mitochondria from microtubules. CDK1 releases dynein through phosphorylation, and Aurora A kinase releases kinesin. When exogenously expressed motors are recruited to mitochondria, it results in asymmetric inheritance of mitochondria, a delay in mitotic progression, and cytokinesis failure. Since mitochondria are initially positioned passively, we were able to manipulate mitochondrial positioning before the onset of mitosis, which persisted into the duration of mitosis. Overall, our study elucidates the mechanism behind mitochondrial inheritance. Undoubtedly, the mechanisms are important for normal inheritance into daughter cells. It remains an open question of whether or not directed inheritance can take place through these same mechanisms.