Mitochondrial transplantation improves recovery in rats after cardiac arrest

When a heart stops beating, blood stops flowing and delivers oxygen to the brain (hypoxia) and other vital organs (ischemia). There is a small window (about 4 minutes) before the lack of blood flow starts damaging the brain. Serious brain damage can be expected after 10 minutes. The sooner the heart can start working again, the less likely there is to be serious brain injury.

Researchers at the Feinstein Institutes for Medical Research have tested a novel approach to increase survival rates, reduce damage and accelerate repair in ischemic brains of rats undergoing mitochondrial transplantation. In an article published in the journal, “Exogenous mitochondrial transplantation improves survival and neurological outcomes after cardiac arrest resuscitation.” BMC medicinethe researchers describe the steps they took from the in vitro laboratory to the in vivo rat model to achieve a 91% survival rate – a 36% improvement over the control.

According to the endosymbiotic theory, mitochondria arose as bacteria that were “swallowed” and formed a symbiotic relationship with the host cell, evolving into the mitochondria within the eukaryotic cells of complex life forms. Nevertheless, the mitochondria have retained some of their ancient bacterial properties. They have double membranes like gram-negative bacteria and the ability to create ATP through aerobic respiration – which requires oxygen – which is why our cells need supplies of oxygen from the blood.

When blood flow and oxygen supply stop, the mitochondria can no longer produce energy and soon the cell is in danger of dying. When the blood has stopped flowing everywhere in the body, the danger is everywhere, but nowhere more so than in the brain.

Recent research has shown that mitochondria can help repair other mitochondria. Injured mitochondria are able to repair themselves and provide cellular protection through fission, fusion and mitophagy. Recently described mechanisms of intracellular mitochondrial transfer have been followed up with mitochondrial transplantation and shown to have protective effects in muscle tissue.

The Feinstein research team decided to test the effectiveness of a transplant in cardiac arrest with a particular focus on neural tissue health.

Before attempting to transfer mitochondria into rats, the researchers wanted to test whether donor mitochondria could be taken up by neurons growing in culture. For this purpose, mitochondria extracted from rat brain and muscle tissue were stained red and mitochondria of the nerve cells green. The donated mitochondria were taken up into cultured neural cells and localized in neural cells along with endogenous mitochondria. After a successful lab test, it was time to try it in a live model.

Thirty-three rats were placed in 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 that might be due to the addition of similar amounts mitochondrial building blocks (proteins, lipids, DNA, RNA) as a fresh sample.

In freshly isolated mitochondrial transplantation, the 72-hour survival rate was 91% compared to only 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 reduced lung injury.

The study demonstrates the underexplored potential of mitochondrial transplantation for tissue protection and repair. A unique aspect of the study was the inclusion of non-functional frozen and thawed mitochondria as an additional control. The frozen and thawed mitochondria had no protective effect, strongly suggesting that the mitochondrial activity of the fresh samples is causal for the protective result.

A very intriguing finding came from gene expression measurements suggesting that fusion genes were significantly downregulated during the recovery period with the freshly transplanted group. Because mitochondrial dynamics have shifted toward fission, the current study appears to be at odds with some previous findings from other research in terms of expected results. That’s exactly the sort of thing that future research wants to explore.