302 Super Mitochondria, the Next Super Therapy to Reverse Ischemic Damage in Stroke?

Abstract

INTRODUCTION: Stroke represents a massive healthcare emergency, ranking in the top 5 causes of death and disability and impacting nearly 800,000 Americans annually. Current therapies are limited. A deeper analysis of the mechanisms of cell death after ischemic brain insult may usher novel safe and effective treatments. Mitochondrial damage serves as a key modulator of ischemic cell death, which may be reversible with transfer of healthy mitochondria from mesenchymal stem cells (MSCs) to ischemic neurons. METHODS: MSCs were grown under ambient condition (normal MSCs) (nMSCs) or metabolic switching paradigm involving exchanging galactose for glucose in the cell culture medium (switched MSCs) (sMSCs) then assayed for oxygen consumption rates using the Seahorse technology. Subsequently, primary neurons were subjected to OGD then co-cultured with either nMSCs or sMSCs, and assessed for cell viability, cell metabolism, mitochondrial reactive oxidative species mRNA, and mitochondrial ATP mRNA. RESULTS: Compared to nMSCs, sMSCs displayed robust mitochondrial respiration as evidenced by higher basal energy production, larger spare respiratory capacity, greater ATP production, and decreased proton (H+) leak. Co-culture of OGD-exposed neurons with sMSCs conferred increased cell viability and enhanced cell metabolism, coupled with reduced mitochondrial reactive oxidative species mRNA and elevated mitochondrial ATP mRNA, which were significantly better than those afforded by nMSCs. CONCLUSIONS: These findings suggest sMSCs generated “super” mitochondria. Metabolic switching produces healthy mitochondria that may enhance the mitochondrial transfer between MSCs and ischemic cells warranting consideration as a stroke therapeutic.