Grant: Discovery Grants Program - Individual

Mitochondria are classically known to be the cellular energy producers. These dynamic organelles can modify their structure by alterations in their fission and fusion activities through the mitochondrial fusion proteins MFN and OPA1, and fission protein DRP1. Mitochondria have the ability to constantly modify their architecture in response to physiological demands and recent discoveries have shown a direct link between mitochondrial structure and function. For example, we have shown that changes in mitochondrial structure, under certain conditions, can modify energy metabolism to promote efficient ATP production while reducing reactive oxygen species (ROS). At the molecular level, the efficiency of mitochondria is modified through enhanced inter-assembly of electron transport chain (ETC) complexes (known as respiratory supercomplexes). However, the molecular mechanism of how changes in mitochondrial dynamics can regulate oxidative phosphorylation is still unknown. The purpose of this proposal is to uncover the basic molecular mechanism of mitochondrial metabolism and how this is regulated by mitochondrial dynamics. We have recently uncovered that the mitochondrial-shaping GTPase protein OPA1 can dictate the bioenergetic status of cells and mitochondrial respiratory capacity by promoting assembly of the electron transport chain (ETC) complexes (C1-C1V) into respiratory super complexes. Manipulation of OPA1, which regulates mitochondrial dynamics, can promote supercomplex assembly to enhance the efficiency of OXPHOS and reduce the generation of damaging ROS. This data provides the first evidence that mitochondrial shaping proteins play a direct role in regulating mitochondrial OXPHOS. In order to identify potential mechanisms by which OPA1 can regulate supercomplex assembly we have performed a proteomic screen using a SILACbased quantitative mass spectrometry (MS) technique. This has uncovered several candidate proteins, including the ETC Complex I assembly factor Cox7RP, that may mediate the molecular changes that OPA1 imposes on metabolism. Cox7RP promotes ETC supercomplex assembly and regulates energy metabolism, and our preliminary data shows that levels Cox7RP respond to changes in expression of mitochondrial OPA1. Therefore, we hypothesis that mitochondrial morphology can regulate OXPHOS through the interaction of the mitochondrial shaping protein OPA1 with Cox7RP. Thus the functional interaction between Cox7RP and the mitochondrial shaping protein OPA1 will be studied to understand the link between mitochondrial morphology and cellular bioenergetic states.