A novel mechanism of mitochondrial protein turnover in Complex I deficient mitochondrial cardiomyopathy

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PROJECT SUMMARY Mitochondria are an important source of reactive oxygen species (ROS). Once thought of inherently bad as it can cause oxidative damage, physiological ROS production is an important signaling molecule. Complex I of the mitochondria is an important source of ROS production and dysfunctional Complex I has been implicated in both mitochondrial disease and in adult-onset metabolic, neurodegenerative, cancer, and cardiac diseases. In fact, Complex I dysfunction is the most common inborn error of metabolism manifests, often resulting in pediatric mitochondrial cardiomyopathies. Our lab has been studying a mouse model of mitochondrial cardiomyopathies to discover mechanisms preserving bioenergetic homeostasis during Complex I impairment. In studying the mitochondrial calcium uniporter (MCU), an important regulator of ATP synthesis, during Complex I dysfunction, we identified a novel form of ROS-dependent protein regulation. We found that under normal circumstances, MCU transiently interacts with Complex I, and physiological ROS production in Complex I leads to MCU turnover. However, during Complex I dysfunction, the Complex I-MCU interaction is abolished, MCU lifespan increases, and this increased lifespan helps preserve mitochondrial bioenergetic homeostasis. We term this mechanism Complex I-induced protein turnover (CLIPT), and hypothesize that CLIPT is a more widespread phenomenon applicable to other mitochondrial proteins. The objective of this proposal is to determine if CLIPT is a mechanism that enables mitochondrial proteins to compensate for disruptions to cardiac mitochondrial homeostasis. In a preliminary screen, we show that a range of mitochondrial proteins may be similarly subject to CLIPT but for this proposal, I will focus on two proteins of interest: Peroxiredoxin3 (PRDX3) and Hydroxy steroid 17-beta dehydrogenase (HSD17B10). PRDX3 and HSD17B10 are interesting candidates in the setting of ROS-induced protein turnover as they play a role in an antioxidant system and in fatty acid metabolism, respectively. In Aim 1, I will demonstrate how PRDX3 and HSD17B10 is also regulated through CLIPT and in Aim 2, define the clinical relevance to upregulation of PRDX3 and HSD17B10 in the context of Complex I dysfunction. Our results may offer new targets for therapies for cardiac mitochondrial disease.