Abstract
Mitochondria play a key role in the homeostasis of the vast majority of the body’s cells. In the myocardium where mitochondria constitute 30 % of the total myocardial cell volume, temporary attenuation or obstruction of blood flow and as a result oxygen delivery to myocardial cells (ischemia) severely alters mitochondrial structure and function. These alterations in mitochondrial structure and function occur during ischemia and continue after blood flow and oxygen delivery to the myocardium is restored, and significantly decrease myocardial contractile function and myocardial cell survival. We hypothesized that the augmentation or replacement of mitochondria damaged by ischemia would provide a mechanism to enhance cellular function and cellular rescue following the restoration of blood flow. To test this hypothesis we have used a model of myocardial ischemia and reperfusion. Our studies demonstrate that the transplantation of autologous mitochondria, isolated from the patient’s own body, and then directly injected into the myocardial during early reperfusion augment the function of native mitochondria damaged during ischemia and enhances myocardial post-ischemic functional recovery and cellular viability. The transplanted mitochondria act both extracellularly and intracellularly. Extracellularly, the transplanted mitochondria enhance high energy synthesis and cellular adenosine triphosphate stores and alter the myocardial proteome. Once internalized the transplanted mitochondria rescue cellular function and replace damaged mitochondrial DNA. There is no immune or auto-immune reaction and there is no pro-arrhythmia as a result of the transplanted mitochondria. Our studies and those of others demonstrate that mitochondrial transplantation can be effective in a number of cell types and diseases. These include cardiac and skeletal muscle, pulmonary and hepatic tissue and cells and in neuronal tissue. In this review we discuss the mechanisms leading to mitochondrial dysfunction and the effects on cellular function. We provide a methodology for the isolation of mitochondria to allow for clinical relevance and we discuss the methods we and others have used for the uptake and internalization of mitochondria. We foresee that mitochondrial transplantation will be a valued treatment in the armamentarium of all clinicians and surgeons for the treatment of varied ischemic disorders, mitochondrial diseases and related disorders.
Highlights
Mitochondria are unique organelles containing their own deoxyribonucleic acid (DNA) that encodes the mitochondrial subunits of the oxidative phosphorylation system
This decrease in cytochrome oxidase would contribute to the diminishment of high energy phosphates. Support for this mechanism comes from 31P nuclear magnetic resonance (NMR) studies in the isolated perfused rabbit heart where we have shown that ischemia induces a significant decrease in phosphocreatine, inorganic phosphate, high energy stores, and high energy synthesis [12]
A role for mitochondrial transplantation In summary, our studies demonstrate that following the onset of myocardial ischemia there are alterations in mitochondrial volume [6], function [6, 8], mitochondrial calcium accumulation [4, 5, 12], mitochondrial enzyme activity [5], mitochondrial complex activity [16], high energy synthesis [6, 8, 12], mitochondrial DNA (mtDNA) [13], the mitochondrial modulated intrinsic cell death pathway [17, 18] and mitochondrial transcriptomics and proteomics [16, 18, 19]
Summary
Mitochondria are unique organelles containing their own DNA that encodes the mitochondrial subunits of the oxidative phosphorylation system. In a series of studies using animal models we and others have demonstrated that ischemia occurring through decreased blood flow to the myocardium significantly alters myocardial mitochondrial structure and function [3,4,5,6,7,8,9].
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