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.

Effects of Mitochondrial Transplantation on Bioenergetics, Cellular Incorporation, and Functional Recovery after Spinal Cord Injury

“…Multiple mechanisms of exogenous mitochondrial incorporation have been proposed, although there is currently no consensus whether it is endocytosis mediated or much more complicated. 71 Mitochondrial uptake is reported following co-incubation with cells in vitro 72,73 or into host cells after direct injection in vivo. 7,59 Conjugation of mitochondria with Pep-1, a cell-penetrating peptide that increases incorporation, further promotes mitochondrial uptake, 45,57,74 and connexins or gap junction-mediated communication appears necessary for cells to take in extracellular mitochondria, [75][76][77] perhaps via actin-dependent processes.…”

“…Mitochondrial transplantation is emerging as a potential therapeutic to maintain mitochondrial function after injury, consequently improving long-term functional outcome. 38 The mechanisms by which transplanted mitochondria exert beneficial effects may Departments of 1 include: increases in ATP production and calcium buffering capacity, decreases in overall ROS production, and generation of a new pool of mitochondrial DNA (mtDNA) (for a review see the study by Gollihue and Rabchevsky 39 ). Although this therapy is relatively new, mitochondrial transplantation is effective in promoting recovery after ischemic injury to cardiac tissue.…”

Mitochondria‐Targeted Antioxidant SkQ1 Prevents Anesthesia‐Induced Dry Eye Syndrome

“…However, the most potent antioxidants are expected to be those targeting ROS directly in their intracellular sources such as mitochondria [ 20 ]. Indeed, intramitochondrial oxidative stress is associated with processes, governing cell survival, such as mitochondrial plasticity, apoptosis, and autophagy [ 21 , 22 ]. Since the mitochondria are impenetrable to conventional antioxidants, the latter have low effectiveness against ROS formation in these organelles.…”

Mesenchymal Stem/Stromal Cell-Mediated Mitochondrial Transfer and the Therapeutic Potential in Treatment of Neurological Diseases

“…Mitochondrial transplantation, either of endogenous or exogenous origin, has shown encouraging outcomes in the replacement of dysfunctional mitochondria [111]. Recently, exogenous mitochondria isolated from PC12 cell line or rat muscle tissues were transplanted into injured rat spinal cord and observed to restore energy supply to injured tissues.…”