Prospects for therapeutic mitochondrial transplantation

Abstract

Mitochondrial dysfunction has been implicated in a multitude of diseases and pathological conditions- the organelles that are essential for life can also be major players in contributing to cell death and disease. Because mitochondria are so well established in our existence, being present in all cell types except for red blood cells and having the responsibility of providing most of our energy needs for survival, then dysfunctional mitochondria can elicit devastating cellular pathologies that can be widespread across the entire organism. As such, the field of "mitochondrial medicine" is emerging in which disease states are being targeted therapeutically at the level of the mitochondrion, including specific antioxidants, bioenergetic substrate additions, and membrane uncoupling agents. New and compelling research investigating novel techniques for mitochondrial transplantation to replace damaged or dysfunctional mitochondria with exogenous healthy mitochondria has shown promising results, including tissue sparing accompanied by increased energy production and decreased oxidative damage. Various experimental techniques have been attempted and each has been challenged to accomplish successful transplantation. The purpose of this review is to present the history of mitochondrial transplantation, the different techniques used for both in vitro and in vivo delivery, along with caveats and pitfalls that have been discovered along the way. Results from such pioneering studies are promising and could be the next big wave of "mitochondrial medicine" once technical hurdles are overcome.

Keywords: Bioenergetics; Cellular uptake; Oxidative phosphorylation; Oxygen consumption; Replacement strategies.

Figure 1. Schematic depiction of how mitochondrial transplantation after injury may promote cell survival

A. During normal cellular function, mitochondria sequester and store calcium in their matrix and produce ATP (1) while NMDA receptors remain closed (2). B. After traumatic injury, the cell is subjected to glutamate excitotoxicity mediated by activated NMDA receptors (3) which allow massive calcium influx into cells (4) and subsequent uptake into mitochondria. This causes a loss of membrane potential across the inner mitochondrial membrane leading to mitochondrial permeability transition pore (MPTP) formation and subsequent swelling of mitochondria (5). Consequent bursting of the outer mitochondrial membrane then releases calcium, ROS, and apoptotic factors (6). ROS damages membrane lipids, mtDNA, electron transport chain proteins, and nuclear DNA (7), which leads to death of adjacent mitochondria (8). C. After healthy mitochondria, depicted in green, are transplanted into damaged cells they can increase antioxidants to combat ROS release (9) and provide new sources of mtDNA (10). Further, these mitochondria increase ATP production (11) and overall calcium buffering capacity (12) in the compromised cells.