ArticleNature communications2023
Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 63 citations in OpenAlex.
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- Targeting PLD3 Reverses the Immunosuppressive Niche by Reprogramming Tumor-Associated Macrophages and Potentiates Antitumor Immunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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- Transfer of Damaged Mitochondria from Cancer Cells to Cancer-Associated Fibroblasts Promotes Tyrosine Kinase Inhibitor Tolerance in EGFR-Mutant Lung Cancer.Cancer research · 2026Article
- Luteolin-Loaded TGN/RAP12 Dual-Peptide Functionalized Nanoparticles: Synergistic Enhancement of BBB Penetration and Microglia Targeting in Alzheimer's Disease.Molecules (Basel, Switzerland) · 2026Article
- Spatially resolved transcriptome-metabolome integration reveals region-specific glial lipid dysregulation associated with Alzheimer's pathology.bioRxiv : the preprint server for biology · 2026Article
- Tmem110 regulates the conformation of TRPML1 to maintain endolysosomal homeostasis and prevent mitochondrial DNA leakage and pathological self-DNA processing.Nature communications · 2026Article
- Mechanistic insights into single-stranded DNA degradation by lysosomal exonucleases PLD3 and PLD4 from structural snapshots.Nature communications · 2025Article
- Targeting Liquid-Liquid Phase Separation and Autophagy in Alzheimer's Disease: Insights into Molecular Mechanisms and Therapeutic Potential.Neurochemical research · 2025Review
- The Role and Therapeutic Potential of the cGAS-STING Signaling Pathway in Alzheimer's Disease.Brain and behavior · 2025Review
- The lysosomal catabolism of nucleic acids-critical regulators of the innate immune system.Nucleic acids research · 2025Review
- Article
- Tripartite Interaction of Epigenetic Regulation, Brain Aging, and Neuroinflammation: Mechanistic Insights and Therapeutic Implications.Epigenomes · 2025Review
- Diverse evolutionary trajectories of mitocoding DNA in mammalian and avian nuclear genomes.Genome research · 2025Article
- Regulation of cGAS-STING signalling and its diversity of cellular outcomes.Nature reviews. Immunology · 2025Review
- Inhibition of the cGAS-STING pathwayChemical science · 2025Article
- Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies.Cell communication and signaling : CCS · 2025Review
- Lysosome repair fails in ageing and Alzheimer's disease.Nature cell biology · 2025Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
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 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.