Thursday, April 18, 2024
4/18/2024
PROJECT SUMMARY: In reperfused myocardial infarction (MI), approximately 50% of cell death is due to reperfusion injury, which still lacks clinical therapies. There is an urgent need to fill in this knowledge gap and to develop novel therapies for this. Initial appropriate mitochondrial quality control is critical for cardioprotection following ischemia/reperfusion (I/R). Mitochondrial homeostasis is tightly regulated by two processes: mitophagy (degradation of damaged mitochondria by autophagy) and mitochondrial biogenesis. Autophagy, an evolutionarily conserved process required for cellular constituent recycling (including mitochondria), is impaired during I/R. Mitochondrial biogenesis is regulated in part by peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1¿). Importantly, mitochondria biogenesis is not increased by I/R injury in the kidney and brain, despite induction of PGC1¿. These results suggest that impaired autophagy/mitophagy following I/R contributes to the attenuation of mitochondrial biogenesis. Enhancing autophagy and mitochondrial biogenesis simultaneously during I/R may therefore restore mitochondrial homeostasis. Consistent with this, our unpublished data show that specific induction of autophagy with Tat-Beclin peptide at the time of reperfusion reduces infarct size in mice, and augments PGC1¿ expression and mitochondrial biogenesis (dependent on the autophagy). Similarly, pharmacological activation of autophagy at the time of reperfusion (using the FDA-approved HDAC inhibitor, SAHA) induces autophagy and PGC1¿ and reduces infarct size >40%. Moreover, SAHA plus PGC1¿ overexpression further increased mitochondrial biogenesis. Studies in the brain have identified Parkin and PARIS as the regulator of PGC1¿ expression. To study Parkinson’s disease, mouse models, and small molecules enhancing Parkin activity are available. Hypothesis: Activation of autophagy confers cardioprotection during I/R through the combined removal of damaged mitochondria and subsequent replacement via PGC1¿-dependent mitochondrial biogenesis, in a Parkin-PARIS dependent manner, and enhancing both processes will afford more effective cardioprotection. Aim 1. To determine whether autophagy is both necessary and sufficient for mitochondrial biogenesis under basal conditions and during cardiac I/R. Aim 2. To define whether autophagy-mediated mitochondrial biogenesis and cardioprotection during I/R are dependent on the Parkin-PARIS-PGC1¿ signaling axis. Aim 3. To establish whether simultaneous enhancement of autophagy/mitophagy and mitochondrial biogenesis during cardiac I/R will augment cardioprotection. Significance and novelty. This study will determine whether autophagy and PGC1¿-dependent mitochondrial biogenesis is critical for reperfusion injury. Clinically, inducing autophagy and mitochondrial biogenesis during the reperfusion is pharmaceutically feasible, which may lead to novel therapies for reperfusion injury. 1
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