Modulation of Mitochondrial calcium uniporter complex in Ischemic Stroke

Abstract

Globally, Stroke ranks as the second leading cause of death. Reperfusion of the ischemic brain also initiates pathologic intracellular cascades that contribute to post-ischemic brain injury. Mitochondrial dysfunction has been known to be a major contributor of neuronal injury during stroke. During reperfusion, [Ca2+]m overload causes mitochondrial ROS overproduction, mitochondrial permeability transition, and activation of cell death signaling cascades. The consequences of mitochondrial calcium overload during stroke has been studied, but the causal upstream mechanisms that leads to calcium overload remains unclear. In the past five years, we1-4 and others have identified the molecular components of the mitochondrial calcium uniporter. The objective of the study was to investigate the expression pattern of uniporter complex during ischemic stroke. Using in-vitro (Oxygen-Glucose deprivation) and in-vivo (murine MCAO) model systems, we investigated in detail, the changes in expression pattern of uniporter components during Hypoxia-Reoxygenation and Ischemia-Reperfusion injury respectively. Finally, we validated our in-vitro and in-vivo findings in human stroke using stroke patient derived post-mortem brain samples. Collectively, data from our study suggests that the unique changes in expression of MCU complex, during reperfusion, results in enhanced [Ca2+]m uptake. The detailed findings of our study will be presented in the conference.