PLD3 depletion and exonuclease dysfunction-causing SNPs promote lysosomal mtDNA build-up. This is accompanied by a lysosomal catabolic impairment and an increased leakiness propensity, leading to TLR9 and STING pathway activation that further promotes autophagy. This results in the accumulation of APP-CTF in autolysosomes, providing additional crosstalk with STING activation, while upregulating SREBP2, and activating de novo cholesterol synthesis. Overall, we identify several feed-forward loops that further confound the degradative capacity of lysosomes, resulting in the accumulation of autolysosomes. A decreased lysosomal Ca 2+ storage/release and a significantly altered lipid composition likely impact as well mitochondria-lysosome MCSs, further propagating the lysosome-centered defects to other organelles, notably mitochondria. Created with BioRender.com.
