Fight Aging!

Mitochondrial function declines with age throughout the body. One of the better explored lines of investigation of this phenomenon focuses on changes in gene expression causing a reduction in mitochondrial fission, leading to impaired mitophagy, in turn leading to a build up of worn and dysfunctional mitochondria. Mitochondria are the descendants of ancient symbiotic bacteria, and they divide (fission) and join together (fusion) like bacteria. Mitophagy is the quality control mechanism responsible for removing damaged mitochondria, and it requires mitochondrial fission in order to operate efficiently, as larger mitochondria are more resistant to mitophagy.

Are there ways to provoke a restoration of youthful levels of mitochondrial fission and thus mitophagy? In one sense yes, in that all of the established approaches to boosting mitochondrial function improve the situation to some degree, such as NAD+ upregulation and mitochondrially targeted antioxidants. In another sense no, as none of those options are definitively better than regular exercise. In a final sense yes, in that researchers have identified various proteins that change in expression with age, affecting mitochondrial fission. It is a long road from identifying a protein to finding a small molecule drug that can safely affect its expression, however, and gene therapies to precisely achieve this sort of outcome throughout the body are still not a going concern.

Today's research materials are an example of this type of work, investigating the mechanisms of mitochondrial fission in search of targets that might improve it in old tissues. It remains to be see what the next generation of therapies aimed at improving mitochondrial function will look like, but it is plausible that transplantation of functional mitochondria, an approach already in preclinical development in several companies, will prove to be a good way to work around the need for a great deal of further research and understanding of mechanisms.

Researchers show protein controls process that goes awry in Parkinson's disease

As scientists work toward finding a cure for Parkinson's disease, one line of research that has emerged focuses on mitochondria, the structures within cells that make energy. The health of those structures is maintained through a quality control system that balances two opposite processes: fission - one mitochondrion splitting in two - and fusion - two becoming one. When there's a problem with fission, that system is thrown out of balance. The consequences can include neurodegenerative diseases, such as Parkinson's disease, and other serious conditions.

A new study found that a protein in humans called CLUH acts to attract Drp1 to mitochondria and trigger fission. In experiments with fruit flies that were genetically engineered with an analog for Parkinson's disease, the team showed that damage from the disease could be reversed by increasing the amount of a protein that scientists call "clueless," which is the fruit fly equivalent of CLUH. "With a critically important pathway such as Drp1, there might be multiple proteins we could use to intervene and ultimately control Parkinson's disease. When we modified clueless in flies, symptoms analogous to Parkinson's disease improved substantially."

The team further showed that both clueless in flies and CLUH in human cells recruit free-floating Drp1 from within a cell to attach to receptors on the surface of mitochondria. In addition, the researchers discovered that CLUH in human cells helps translate the genetic instructions found in messenger RNA into the protein for Drp1 receptors on the surface of mitochondria. More available Drp1 receptors means that more Drp1 can be recruited in order to trigger fission.

Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria

Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation.

Importantly, drp1 overexpression rescues adult lethality, tissue disintegration, and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.