Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury.
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.
Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Akihiro
A
Masuzawa
Kendra M
KM
Black
Christina A
CA
Pacak
Maria
M
Ericsson
Reanne J
RJ
Barnett
Ciara
C
Drumm
Pankaj
P
Seth
Donald B
DB
Bloch
Sidney
S
Levitsky
Douglas B
DB
Cowan
James D
JD
McCully
D000818:Animals; D017209:Apoptosis; D003402:Creatine Kinase / Q000378:metabolism; D004452:Echocardiography; D005110:Extracellular Space / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000637:transplantation*; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D014182:Transplantation, Autologous; D014336:Troponin / Q000032:analysis / Q000378:metabolism; D056969:Voltage-Sensitive Dye Imaging
D014336:Troponin; D003402:Creatine Kinase