Novel Signaling Mechanisms in the Regulation of Mitochondrial Dynamics

Abstract

Mitochondria are dynamic organelles that constantly undergo fission and fusion events (referred to as mitochondrial dynamics) to form highly interconnected networks within cells. These networks allow mitochondria to share resources such as mitochondrial DNA and antioxidant molecules to maintain the health of the network. Because mitochondria are the main source of production of ATP through oxidative phosphorylation, and also regulate cell death through apoptosis, it is critically important to maintain homeostasis in these organelles. Indeed, dysfunction in mitochondrial dynamics has been linked to numerous diseases, including cancer, neurodegenerative, endocrine, and cardiovascular diseases. Therefore, understanding the mechanisms by which mitochondrial dynamics contributes to the overall health of this organelle is of great interest. The primary proteins involved in the regulation of mitochondrial fusion and fission, and the mechanisms by which they act, are generally understood. It is also well accepted that mitochondrial fusion and fission is balanced; however, how these two separate processes communicate and signal to each other is currently unknown. To better understand the crosstalk between mitochondrial fission and fusion, we studied a function of the outer mitochondrial membrane associated E3 ubiquitin ligase, MARCH5. We found that MARCH5 acts as a negative regulator of mitochondrial fission through the ubiquitin-dependent degradation of the fission factor, MiD49. Shedding light on a possible mechanism by which the activities of fission factors are coordinated, we found that the Drp1 receptor, Mff, promotes MiD49 stability by negatively regulating MARCH5 activity, thereby enhancing mitochondrial fission rates. Finally, supporting molecular crosstalk between fission and fusion, we found that Mff also regulates the stability of the outer mitochondrial membrane fusion factors, Mfn1 and Mfn2, and that loss of Mff expression/activity results in reduced mitochondrial fusion rates in those cells. Thus, the studies presented here display novel crosstalk and signaling mechanisms by which fission factors are able to fine-tune mitochondrial fission and fusion rates through modification of the ubiquitin-proteasome system.