Journal Article

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

Bretou, Marine, Perdok, Anika, Dehairs, Jonas, Sannerud, Ragna, Swinnen, Johannes V., Annaert, Wim, Damme, Markus, Van Acker, Zoë P., Hellemans, Ruben, North, Katherine, Vorsters, Inge, Cappel, Cedric

2023

Overview

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 as how a defective lysosomal nucleotide catabolism connects to AD-proteinopathy. We identified mitochondrial DNA (mtDNA) as a major physiological substrate and show its manifest build-up in lysosomes of PLD3-defective cells. mtDNA accretion creates a degradative (proteolytic) bottleneck that presents at the ultrastructural level as a marked abundance of multilamellar bodies, often containing mitochondrial remnants, which correlates with increased PINK1-dependent mitophagy. Lysosomal leakage of mtDNA to the cytosol activates cGAS–STING signaling that upregulates autophagy and induces amyloid precursor C-terminal fragment (APP-CTF) and cholesterol accumulation. STING inhibition largely normalizes APP-CTF levels, whereas an APP knockout in PLD3-deficient backgrounds lowers STING activation and normalizes cholesterol biosynthesis. Collectively, we demonstrate molecular cross-talks through feedforward loops between lysosomal nucleotide turnover, cGAS-STING and APP metabolism that, when dysregulated, result in neuronal endolysosomal demise as observed in LOAD. Phospholipase D3 polymorphisms are linked to late-onset Alzheimer’s disease but the mechanisms are not understood. Van Acker and colleagues show that Phospholipase D3 processes mitochondrial DNA in lysosomes to maintain lysosomal homeostasis and proper degradation of the amyloid precursor protein.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/19 / 14/28 / 38/71 / 631/378/87 / 631/80/304 / 631/80/313/1624 / 631/80/39/2348 / 82/1 / 82/80 / 96/31 / Alzheimer's disease / Amyloid precursor protein / Amyloidogenic Proteins / Autophagy / Biosynthesis / Catabolism / Cholesterol / Chromogranin A / Cytosol / Degradation / Deposition / DNA, Mitochondrial / Exonuclease / Homeostasis / Humanities and Social Sciences / Lysosomes / Metabolism / Mitochondria / Mitochondrial DNA / multidisciplinary / Neurodegenerative diseases / Nucleotides / Nucleotidyltransferases / Phospholipase / Phospholipases / Precursors / Protein turnover / Proteolysis / PTEN-induced putative kinase / Science / Science (multidisciplinary) / Signaling / Substrates