Abstract Body: Introduction: During cardiac ischemic events, mitochondria play a critical role in modulation of necrosis and myocardial recovery. One contentious strategy to address mitochondrial dysfunction during ischemia-reperfusion injury is the transplantation of viable, respiration-competent mitochondria into the heart by direct injection or even systemic vascular infusion. Despite translational interest, evidence supporting the efficacy of this approach remains uncertain: mainly how exogenous mitochondria might survive extracellular transplantation, integrate into cardiomyocyte mitochondrial networks, and supply sufficient energy to protect an injured heart. Our objective is to address whether exogenous mitochondria survive after transplantation and to identify the mechanisms underlying cardioprotection.
Methods/Results: Viable mitochondria from the heart and skeletal muscle of healthy, adult C57BL/6J mice were isolated and exposed to plasma or myocardial extracellular fluid (ECF) for 1 hour, both of which resulted in Ca²⁺ induced swelling, rupture and loss of respiratory capacity. Blockade of Ca²⁺ uptake with the MCU Ca²⁺ uptake inhibitor Ru360 results in prevention of mitochondrial swelling with plasma or ECF exposure but is not sufficient to prevent respiratory capacity deficits.
Conclusions: Our studies suggest that once transplanted into an extracellular space, previously viable isolated mitochondria become dysfunctional and are unable to have a meaningful physiologic effect on injured tissues. Additionally, we observe that intramyocardial injection of isolated mitochondria results in short-term clearance. Ischemia reperfusion injury with mitochondrial transplantation strategies using genetic double labeling in vivo are underway to elucidate the final fate of transplanted mitochondria, any functional consequences, and the contribution of inflammation in this process.