Mitochondrial Division Promotes Regeneration of Damaged Tissue: New Study Shows

A recent paper published in the journal Cell Stem Cell has documented how mitochondrial division is vital in the regeneration of damaged tissue in muscle stem cells.

The scientists began their experiments by carrying out gene expression analysis on muscle stem cells derived from injured and uninjured mice. Moreover, the scientists upregulated the pathways relating to both cellular division and the generation of energy in the cells sampled one and three days after injury.

Interestingly, they reported that the upregulation of Drp1—a gene associated with mitochondrial fission—translated to mitochondria growing to medium and large sizes one day after injury. And three days after injury, the mitochondria were small again, implying rapid growth and division. As for the inactive stem cells, their mitochondria remained small. 

To determine how much Drp1 and mitochondrial fission was required for stem cell proliferation, the researchers used a strain of mice that exhibited an impairment in Drp1 expression. While there was very little difference and evidence of dysfunction in stem cells that were inactive, proliferation after injury formed abnormalities in the altered mice. 

Compared to control stem cells, these muscle stem cells had abnormally long and dysfunctional mitochondria, and exhibited more reactive oxygen species. They also failed to transition towards oxidative phosphorylation—an energetic process of respiration. Their gene expression was also less proliferated, and at a macro level, these mice displayed smaller muscle fibers, even two weeks after injury. 

Mitophagy (mitochondrial recycling through autophagy) was also disrupted in the modified mice. Because despite the Parkin signal for mitophagy being upregulated, the signal was not being taken up correctly by the impaired mitochondria, and instead, accumulated in the cytoplasm. 

In the second part of the study, researchers attempted to treat these mitochondrial fission-impaired cells by stopping mitochondrial fusion through silencing of the necessary RNA to see if it would have any effects. While this process somewhat normalized mitochondria in these cells and enhanced their proliferation and ability to form muscle fibers, it damaged cells taken from mice in the wild. 

The scientists also documented that using dichloroacetate to restore oxidative phosphorylation and rapamycin to promote autophagy were helpful in restoring the cells’ proliferative capabilities. 

This approach was also observed to be helpful to muscle stem cells derived from wild-type mice, enhancing their regenerative abilities. In conclusion, the researchers noted that the older cells had more problems, such as inflammation, when compared to the Drp1 impaired cells of modified young animals.

This research combines two hallmarks of aging, stem cell exhaustion and mitochondrial dysfunction, and how they correlate in very specific ways. It’s the first study of its kind, and seeks a solution to a very thoughtful problem. Indeed, if mitochondria in muscle stem cells can safely be introduced in human beings through small treatments, the research might lead to the treatment of age-related muscle-loss known as sarcopenia.