Mitochondrial transplantation improves rat recovery from cardiac arrest

When the heart ceases to beat, the circulation of blood also stops, leading to insufficient delivery of oxygen to the brain (hypoxia) and other essential organs (ischemia). Within a short period of around four minutes, the lack of blood flow can begin to damage the brain. If the cessation of blood flow persists for 10 minutes or more, severe brain damage is highly probable. Restarting the heart as soon as possible is critical in reducing the risk of significant brain injury.

A new study conducted by researchers at the Feinstein Institutes for Medical Research details a novel approach to improve survival rates, reduce damage and speed up repair in rats' ischemic brains through mitochondrial transplantation. The researchers' findings, published in BMC Medicine under the title "Exogenous mitochondrial transplantation improves survival and neurological outcomes after resuscitation from cardiac arrest," showcase the steps taken from in vitro lab to in vivo rat models. The study revealed a 91% survival rate, marking a 36% improvement over the control group.

Based on the endosymbiotic theory, mitochondria are believed to have evolved from a bacterium that was "engulfed" and established a symbiotic relationship with the host cell, eventually becoming the mitochondria that exist within the eukaryotic cells of complex organisms. However, even after this evolution, mitochondria have retained some of their ancient bacterial traits, such as their double membranes resembling those of gram-negative bacteria and their ability to produce ATP through aerobic respiration, which requires oxygen. This is why our cells require oxygen supply from the bloodstream.

When the flow of blood is interrupted and oxygen supply ceases, the mitochondria lose their ability to generate energy, placing the cell at risk of death. In such scenarios, if the blood flow is obstructed throughout the body, the danger is widespread, particularly in the brain.

Recent research has shown some promise for mitochondria being able to assist in the repair of other mitochondria. Injured mitochondria are capable of self-repair and cellular protection through fission, fusion, and mitophagy. Recently described mechanisms of intercellular mitochondrial transfer have been followed up with mitochondrial transplantations and were shown to have protective effects in muscular tissues.

The Feinstein research team decided to test the effectiveness of transplantation in a cardiac arrest event with a specific focus on neuronal tissue health.

The researchers aimed to evaluate whether donor mitochondria could be integrated into neurons growing in culture, prior to transferring them into rats. For this purpose, they stained mitochondria extracted from rat brain and muscle tissues in red, while the mitochondria of neural cells were stained green. The results demonstrated that the donated mitochondria were incorporated into cultured neural cells and co-localized with the endogenous mitochondria within these cells. The success of this laboratory test paved the way for its implementation in a live model.

Thirty-three rats were put into cardiac arrest for 10 minutes and then resuscitated and given one of three treatments: freshly isolated donor mitochondria, negative control solution, and nonfunctional (frozen/thawed) mitochondria to look for effects potentially due to adding similar amounts of mitochondrial building blocks (proteins, lipids, DNA, RNA) as the fresh sample.

In freshly isolated mitochondria transplantation the 72-hour survival rate was 91% compared to just 55% in the negative control. The excellent survival rates were associated with improvements in rapid recovery of arterial lactate, glucose levels, cerebral microcirculation, neurological function and decreased lung injury.

The study highlights the unexplored potential of mitochondrial transplantation in tissue protection and recovery. An interesting aspect of the study was the use of nonfunctional frozen-thawed mitochondria as an additional control. Notably, the frozen-thawed mitochondria failed to confer any protective effect, strongly implying that the preservation of mitochondrial activity in fresh samples is a causal factor in the observed protective outcome.

The study yielded a fascinating discovery through gene expression measurements, indicating a notable reduction in fusion genes during the recovery phase in the group that received fresh transplantation. The shift in mitochondrial dynamics towards fission observed in this study contrasts with some prior research, presenting an unexpected outcome. Such discrepancies in results may warrant further investigation in future research.