Targeting the mitochondrial protein mitoNEET for the treatment of reperfusion-injury after stroke

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PROJECT SUMMARY Stroke is the fifth leading cause of death and the leading cause of disability in the United States. There remains a critical need for innovative therapeutic approaches that can successfully prevent or reverse brain injury following stroke. Dysfunction of the mitochondrial biochemistry following ischemic stroke and reperfusion injury contributes to significant neuronal cell loss; however, the development of therapeutics targeting mitochondrial function for stroke patients are lacking. Mitochondrial dysfunction plays a central role in the neuronal cell death seen in ischemia-reperfusion injury, but has not yet been fully investigated as drug target. In this project, we are investigating novel mitochondrial protein mitoNEET as therapeutic drug target of mitochondrial function in stroke. MitoNEET is a newly discovered protein that regulates mitochondrial bioenergetics. We developed a first-in- class mitoNEET agonist NL-1 which showed significant tissue protection after transient ischemia in the brain. The objectives of this proposal are to evaluate a recently discovered mitochondrial protein, mitoNEET, as an effective therapeutic approach for the pharmacological treatment of stroke. MitoNEET (CISD1 gene) regulates mitochondrial bioenergetics capacity where it functions as redox sensor. Our central hypothesize is that ligands selectively binding to mitoNEET will protect brain tissue from hypoxia-induced reperfusion injury, by reducing mitochondrial dysfunction and oxidative stress. In our first aim, we will determine the pharmacological effect of the mitoNEET ligands in a mouse model of middle cerebral ischemic reperfusion injury, and evaluate the duration of the therapeutic window of the mitoNEET agonists where compounds will still be effective in preventing neuronal cell death if given after a reperfusion injury. In the second aim, we will develop potent and selective mitoNEET ligands with blood-brain barrier permeability properties. Predicted outcomes are that mitoNEET agonists will be neuroprotective in stroke. These findings will have far-reaching implication for developing neuroprotective medications as a treatment strategy for limiting the mitochondrial contribution to cell loss in the clinical setting in the treatment of stroke patients.