Mitochondrial transplantation for therapeutic use

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.

Transit and integration of extracellular mitochondria in human heart cells

“…A complete understanding of the mechanisms that bring about endocytosis of extracellular mitochondria and fusion of those organelles with the endogenous mitochondrial network may provide a foundation for innovative new treatments to a number of human diseases and disorders 35 . Our earlier work has supported the use of mitochondrial transplantation to decrease infarction, increase ATP content, and improve functional performance of the ischemic heart 6–9,17 . We also demonstrated that delivery of exogenous mitochondria to the heart in animal models does not provoke an immune response nor produce arrhythmias 7,21 .…”

“…When combined with the findings of other investigators, our results strongly support the notion that the uptake and subsequent fusion of extracellular mitochondria with recipient cell mitochondria is an evolutionarily-conserved and pervasive biological process 7–16 . A thorough understanding of the intracellular fate of exogenous mitochondria may present new treatment strategies for the ischemic heart and drive the development of organelle-based therapeutics for a host of other human diseases and disorders 17–20 .…”

Artificial Mitochondria Transfer: Current Challenges, Advances, and Future Applications

“…Investigators currently use the terms mitochondria transformation [9], transfer [93], and transplant [117, 181] interchangeably to designate the artificial transport of mitochondria from one cell to another via diverse methodologies. According to our criteria, the term that best defines this process is transfer .…”

Alternative Methods for Mitochondrial Transplantation: Efficiency of Unpackaged and Lipid-Packaged Preparations

“…There are benefits to be gained by exploring and comparing techniques that could be applied to enhance mitochondrial activity in large numbers of cells, as might be used in tissue repair to address mitochondrial deficits that underlie many common disorders, such as disease or aging related dysfunctions of brain and muscle. Several groups have begun experiments with such techniques, in culture, as here, and by injection of mitochondrial preparations into tissue (15,18). The results presented here suggest that for those purposes, exposure of cells to substantially pure mitochondrial preparations packaged in lipids that match cell membranes may produce greater uptake of mitochondria by recipient cells than the use of unpackaged mitochondria.…”