How Mitochondria Selectively Remove Damaged Mitochondrial DNA
Mitochondrial DNA becomes damaged more readily than nuclear DNA, as the systems of DNA repair in mitochondria are less effective, and the DNA structures are less well protected. Some forms of mitochondrial DNA damage can cause mitochondria to become dysfunction while also replicating more efficiently than their peers, leading to pathological cells overtaken by pathological mitochondria that cause damage to their surroundings. As an opposing force, there appear to be ways in which mitochondria can selectively eliminate damaged DNA under some circumstances. Can these mechanisms be meaningfully enhanced to reduce mitochondrial DNA damage and its consequences in aging?
Understanding the mechanisms governing selective turnover of mutation-bearing mitochondrial DNA (mtDNA) is fundamental to design therapeutic strategies against mtDNA diseases. Here, we show that specific mtDNA damage leads to an exacerbated mtDNA turnover, independent of canonical macroautophagy, but relying on lysosomal function and ATG5. Using proximity labeling and Twinkle as a nucleoid marker, we demonstrate that mtDNA damage induces membrane remodeling and endosomal recruitment in close proximity to mitochondrial nucleoid sub-compartments.
Targeting of mitochondrial nucleoids is controlled by the ATAD3-SAMM50 axis, which is disrupted upon mtDNA damage. SAMM50 acts as a gatekeeper, influencing BAK clustering, controlling nucleoid release and facilitating transfer to endosomes. Here, VPS35 mediates maturation of early endosomes to late autophagy vesicles where degradation occurs.
In addition, using a mouse model where mtDNA alterations cause impairment of muscle regeneration, we show that stimulation of lysosomal activity by rapamycin, selectively removes mtDNA deletions without affecting mtDNA copy number, ameliorating mitochondrial dysfunction. Taken together, our data demonstrates that upon mtDNA damage, mitochondrial nucleoids are eliminated outside the mitochondrial network through an endosomal-mitophagy pathway. With these results, we unveil the molecular players of a complex mechanism with multiple potential benefits to understand mtDNA related diseases, inherited, acquired or due to normal ageing.
If there was sufficiently different DNA for 2 Mitochondria could each one identify the other as different and fight for cellular dominance?
If so would natural DNA drift in the mitochondria cause them to begin to fight all over the body as we get older?