Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury

Abstract

Mitochondrial damage and dysfunction occur during ischemia and modulate cardiac function and cell survival significantly during reperfusion. We hypothesized that transplantation of autologously derived mitochondria immediately prior to reperfusion would ameliorate these effects. New Zealand White rabbits were used for regional ischemia (RI), which was achieved by temporarily snaring the left anterior descending artery for 30 min. Following 29 min of RI, autologously derived mitochondria (RI-mitochondria; 9.7 ± 1.7 × 10(6)/ml) or vehicle alone (RI-vehicle) were injected directly into the RI zone, and the hearts were allowed to recover for 4 wk. Mitochondrial transplantation decreased (P < 0.05) creatine kinase MB, cardiac troponin-I, and apoptosis significantly in the RI zone. Infarct size following 4 wk of recovery was decreased significantly in RI-mitochondria (7.9 ± 2.9%) compared with RI-vehicle (34.2 ± 3.3%, P < 0.05). Serial echocardiograms showed that RI-mitochondria hearts returned to normal contraction within 10 min after reperfusion was started; however, RI-vehicle hearts showed persistent hypokinesia in the RI zone at 4 wk of recovery. Electrocardiogram and optical mapping studies showed that no arrhythmia was associated with autologously derived mitochondrial transplantation. In vivo and in vitro studies show that the transplanted mitochondria are evident in the interstitial spaces and are internalized by cardiomyocytes 2-8 h after transplantation. The transplanted mitochondria enhanced oxygen consumption, high-energy phosphate synthesis, and the induction of cytokine mediators and proteomic pathways that are important in preserving myocardial energetics, cell viability, and enhanced post-infarct cardiac function. Transplantation of autologously derived mitochondria provides a novel technique to protect the heart from ischemia-reperfusion injury.

Polymer Functionalization of Isolated Mitochondria for Cellular Transplantation and Metabolic Phenotype Alteration

“…The benefits of compensatory endogenous mitochondrial transfer through extracellular spaces into metabolically compromised cells in a variety of prevalent acquired diseases provided the impetus for investigating mitochondrial transplantation as a viable treatment approach by our laboratory as well as by other groups 26. To determine whether transplantation of polymer‐functionalized mitochondria was capable of triggering a bioenergetic switch in cells of varying origin and phenotype, simultaneous OCR and ECAR were assessed.…”

Modifying the Mitochondrial Genome

“…Autologous mitochondria were injected into a rabbit model of regional ischemia and improved recovery from the injury (Masuzawa et al, 2013). Data showed that most of the injected mitochondria remained extracellular with some mitochondria taken up by cells, although it was unclear how mitochondria were taken up from the extracellular fluid (Masuzawa et al, 2013). …”

State-of-the-Art Methods for Evaluation of Angiogenesis and Tissue Vascularization

“…Additionally, the LAD is occluded just distal to the first diagonal. 127,128 The intervention can be performed at any time point but commonly occurs just before and after reperfusion.…”