Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism

• DOI: 10.1038/s41467-023-38501-w
• Publication Date: 2023-05-24T10:03:34Z
• Authors: Zoë P. Van Acker; Anika Perdok; Ruben Hellemans; Katherine North; Inge Vorsters; Cedric Cappel; Jonas Dehairs; Johannes V. Swinnen; Ragna Sannerud; Marine Bretou; Markus Damme; Wim Annaert
• Keywords: Nucleotides; Phospholipases; Science; Q; Chromogranin A; Amyloidogenic Proteins; DNA, Mitochondrial; Nucleotidyltransferases; Article; Mitochondria

Abstract Phospholipase D3 (PLD3) polymorphisms are linked to late-onset Alzheimer’s disease (LOAD). Being a lysosomal 5’-3’ exonuclease, its neuronal substrates remained unknown as well how defective nucleotide catabolism connects AD-proteinopathy. We identified mitochondrial DNA (mtDNA) major physiological substrate and show manifest build-up in lysosomes of PLD3-defective cells. mtDNA accretion creates degradative (proteolytic) bottleneck that presents at the ultrastructural level marked abundance multilamellar bodies, often containing remnants, which correlates with increased PINK1-dependent mitophagy. Lysosomal leakage cytosol activates cGAS–STING signaling upregulates autophagy induces amyloid precursor C-terminal fragment (APP-CTF) cholesterol accumulation. STING inhibition largely normalizes APP-CTF levels, whereas an APP knockout PLD3-deficient backgrounds lowers activation biosynthesis. Collectively, we demonstrate molecular cross-talks through feedforward loops between turnover, cGAS-STING metabolism that, when dysregulated, result endolysosomal demise observed LOAD.