Interaction of mitochondrial fusion and transmembrane potential in diabetic cardiovascular damage

University Of Texas Rio Grande Valley, Edinburg TX

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Abstract

PROJECT SUMMARY/ABSTRACT This proposal explores the interaction of mitochondrial fusion dynamics and transmembrane potential (∆ψm) as an underlying mechanism and translational target in diabetic cardiovascular damage. Type 2 diabetes mellitus is a rapidly-increasing public health concern, causing decreased cardiac efficiency which is the leading cause of mortality among Type 2 diabetics. A range of clinical and experimental data suggests that the cytokine-mediated inflammation that drives diabetic pathology directly damages mitochondria, the organellar network responsible for cellular bioenergetics. Crucially, however, it is unknown what level of mitochondrial damage can be sustained in highly-oxidative cardiac cells before pathology ensues. Our current SC3 support has provided novel mechanistic insights motivating the proposed aims: 1) to explore how the OMA1 stress-responsive protease is activated by loss of ∆ψm, 2) the role of OPA1 levels in determining mitochondrial fusion homeostasis, and 3) the time-dependent nature of ∆ψm-sensitive mitochondrial fusion dynamics. These experiments will leverage our published cell-based imaging and functional assays to further explore this gap in knowledge. To maintain bioenergetic homeostasis, mitochondria balance their organization between a united, reticular network (OPA1-mediated fusion) and a fragmented population of individual organelles (DRP1-mediated fission). The ∆ψm across the mitochondrial inner membrane is required for mitochondrial fusion, linking organellar function and structural dynamics: we demonstrated previously that a sharply-defined threshold of 34% ∆ψm is required for mitochondrial fusion. Strikingly, our current data indicates that a similar threshold exists in cardiac-derived cells, and that this threshold is mediated by OMA1, a stress- response protease that cleaves the mitochondrial OPA1 fusion protein in response to low ∆ψm. Further, our data suggests that novel intramolecular domains are required for OMA1 to sense loss of ∆ψm. Our project will mechanistically explore this threshold, as well as the impacts of cytokine-mediated damage on ∆ψm and fusion dynamics and the time-integrated nature of mitochondrial stress-sensitive dynamics. This research has strong potential to inform a novel translational approach to protect cardiac mitochondria against cytokine-mediated damage.