Friday, May 3, 2024
5/3/2024
Project Summary/Abstract Mitochondrial dysfunction is the main mechanism contributing to cell death and tissue damage in cerebral ischemia-reperfusion injury (I/R). Calcium-induced mitochondrial swelling, uncoupling of respiration, and cell death occur in mammals under hypoxic conditions of I/R. These changes are due to the activation of the mitochondrial megachannel also known as the mitochondrial permeability transition pore (mPTP). Remarkably, the embryos of the mysterious organism, brine shrimp Artemia franciscana, tolerate anoxic conditions for several years and were reported to lack hypoxia and Ca2+-activated mPTP opening. mPTP was at the center of scientific research for several decades and it still remains one of the most mysterious phenomena in biology today due to the lack of information about its exact molecular composition, structure, and regulatory mechanisms. Recently, mammalian ATP synthase was shown to undergo calcium-induced conformational changes to form an uncoupling channel with the biophysical properties of mPTP. In this proposal, we will use single-particle cryo- electron microscopy (cryo-EM) to identify the high-resolution structure and activation/inactivation mechanisms of Artemia franciscana ATP synthase. These studies will reveal the distinct structural features of Artemia ATP synthase that prevent the Ca2+ and hypoxia-induced mitochondrial dysfunction and cell death in this organism. Successful completion of this proposal will help to unlock the development of specific and potent therapeutic compounds targeting mammalian ATP synthase leak channel for treating I/R injury and other mPTP-related diseases.
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