During mitosis, cellular processes such as organelle trafficking cease, and instead, the cell focuses on segregating chromosomes into daughter cells4,5. However, proper cellular function also requires the partitioning of organelles. The mechanism behind ER, Golgi apparatus, and peroxisomes inheritance among others are better understood, but to date, that of mitochondrial segregation remains unknown6-8. During interphase, mitochondria move along microtubules through the motor-adaptor complex, consisting of Miro, which localizes to the mitochondrial outer membrane, the adaptor Milton, and Kinesin Heavy Chain and Dynein motors9,10. As the cell proceeds to mitosis, mitochondria detach from microtubules and remain unattached until mitosis is completed2,11,12. The proposed study will investigate the mechanism behind mitochondrial release from microtubules during mitosis. Potential contributors to mitochondrial detachment during mitosis include calcium regulation of Miro and APC/C-mediated degradation of Miro. Calcium is of particular interest since it is a known regulator of mitochondrial motility, and intracellular calcium increases during mitosis. Another attractive explanation of mitochondrial release is by Miro degradation. In a mass spectroscopy analysis of the cell cycle, Miro levels decreased during mitosis and G1 phases. Additionally, Miro contains a conserved APC/C-targeted destruction box motif that has yet to be verified1. In addition to investigating the roles of calcium and Miro's destruction box, the proposed study will examine protein level changes that associate with the mitochondrial detachment during mitosis. As a whole, this study will further the field's understanding of mitochondrial inheritance in particular how the mitochondria are released from mitotic microtubules.
This proposal will investigate the mechanism behind mitochondrial distribution during mitosis, in particular how mitochondria release from microtubules. Normally, mitochondria are attached to microtubules through the motor adaptor complex made of Miro/Milton/KHC/Dynein. Understanding how the motor adaptor complex is regulated during mitosis will provide answers to this key fundamental question in cell biology.
|Chung, Jarom Yan-Ming; Steen, Judith Arunodhaya; Schwarz, Thomas Lewis (2016) Phosphorylation-Induced Motor Shedding Is Required at Mitosis for Proper Distribution and Passive Inheritance of Mitochondria. Cell Rep 16:2142-2155|