Scientists at the University of Cologne have discovered how cells can specifically eliminate mutated mitochondrial DNA (mtDNA). Mitochondria are the power plants of our cells and, due to their evolutionary descent from bacteria, still have genetic material packaged in chromosome-like structures (nucleoids). They convert the chemical energy in our food into a biologically usable form. In their work, the researchers show that mutations of the mtDNA lead to a local rearrangement of proteins in the mitochondrial membrane. The mutated mtDNA is thus specifically eliminated and sent to autophagy, the cellular "garbage disposal". Researchers from the Center for Physiology of the Medical Faculty of the University of Cologne, the Center for Molecular Medicine Cologne (ZMMK) and the Cluster of Excellence for Aging Research CECAD were involved in the study. The results have been published in the article "Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA" in Nature Communications.
In many tissues, mutations in mtDNA accumulate as a result of normal aging. Such mutations are then an important cause of many age-related diseases. mtDNA is present in thousands of copies per cell, so mitochondrial function is impaired only when the percentage of mutated mtDNA molecules exceeds a threshold level. It has long been known that mitochondrial damage, including acute mtDNA damage, triggers the process of mitophagy. In this process, dysfunctional mitochondrial parts are selectively degraded and recycled.
Dr. David Pla-Martin, the lead author of the current study, explains the details, "What is new in our study is that this mechanism does not affect the cells' endowment of mitochondria, but only purges them of damaged mtDNA. Using labeling of neighboring proteins - so-called proximity labeling - we were able to show that mtDNA damage leads to the recruitment of endosomes in close proximity to nucleoids." Their removal is coordinated by the interaction of the nucleoid protein Twinkle and the mitochondrial membrane proteins SAMM50 and ATAD3. In this process, ATAD3 controls their distribution, and SAMM50 induces the release and transfer of the nucleoid to the so-called endosomes. "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 occur," Pla-Martin said.
Using a mouse model in which mtDNA mutations lead to impaired muscle regeneration, the scientists* also showed that selectively mutated mtDNA can be removed by stimulating the activity of the autophagy machinery with rapamycin. The total number of mtDNA copies thus remains constant, preserving mitochondrial function.
Prof. Dr. Rudolf Wiesner, head of the group, adds: "Mutations in the genes encoding these proteins lead to severe neurological diseases, in the case of 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 such age-related diseases." Although the road to therapeutic application may still be long, the research team sees this as a promising approach.
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To the publication:
https://www.nature.com/articles/s41467-022-34205-9