Waste disposal mechanism of mitochondria to remove mtDNA mutations

University of Cologne researchers have uncovered the mechanism by which cells can get rid of mutated mitochondrial DNA (mtDNA)—the heart of each of our cells, the mitochondria. They still have genetic material packaged in structures resembling chromosomes because of their evolutionary descent from bacteria (nucleoids).

The food’s chemical energy is transformed by them into a form that can be utilized by living things.

The Physiology Centre at the Faculty of Medicine of the University of Cologne, the Centre for Molecular Medicine Cologne (CMMC), and the CECAD Cluster of Excellence for Aging Research have now demonstrated how mutations in the mtDNA result in a local rearrangement of proteins in the mitochondrial membrane.

The cellular “waste disposal” process, known as autophagy, is used to target, eliminate, and process the mutated mtDNA. The study’s findings were published in Nature Communications.

As a result of normal aging, mtDNA mutations build up in many tissues. These types of mutations play a significant role in the development of many diseases linked to aging. Every cell contains thousands of copies of mtDNA, so mitochondrial dysfunction only occurs when the proportion of mutated mtDNA molecules exceeds a predetermined threshold.

It has long been known that mitophagy is triggered by mitochondrial damage, including acute mtDNA damage. Selective degradation and recycling of damaged mitochondrial components occur during this process.

What is new in our study is that this mechanism does not affect the cells’ endowment with mitochondria, but only clears out the damaged mtDNA. By labeling neighboring proteins—so-called proximity labeling—we showed that mtDNA damage leads to the recruitment of endosomes in close proximity to nucleoids.”

Dr David Pla-Martin, Study Lead Author and Postdoctoral Researcher, University of Cologne

The interaction between the mitochondrial membrane proteins SAMM50 and ATAD3 and the nucleoid protein Twinkle orchestrates their elimination. While SAMM50 causes the release and transfer of the nucleoid to the so-called endosomes, ATAD3 regulates their distribution.

Dr Pla-Martin added, “This additionally prevents the activation of an immune response. The protein VPS35, the main component of the retromer, mediates the maturation of early endosomes into late autophagy vesicles, where degradation and recycling ultimately take place.”

The researchers also demonstrated that specifically mutated mtDNA can be eliminated by activating the autophagy mechanism with rapamycin using a mouse model in which mtDNA mutations result in impaired muscle regeneration. As a result, the overall number of mtDNA copies stays constant, maintaining mitochondrial function.

Mutations in the genes that code for these proteins lead to severe neurological diseases, in VPS35 for example Parkinson’s disease. We now want to use these proteins as new molecular targets to open up entirely new treatment options for these kinds of aging-associated diseases.”

Dr Rudolf Wiesner, Associated Principal Investigator, Department of Physiology, University of Cologne

The research team believes that this is a promising strategy, even though the path to the therapeutic application could be long.