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

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 and Wim Annaert ()
Additional contact information
Zoë P. Van Acker: VIB Center for Brain & Disease Research
Anika Perdok: VIB Center for Brain & Disease Research
Ruben Hellemans: VIB Center for Brain & Disease Research
Katherine North: VIB Center for Brain & Disease Research
Inge Vorsters: VIB Center for Brain & Disease Research
Cedric Cappel: Christian-Albrechts-University Kiel
Jonas Dehairs: KU Leuven
Johannes V. Swinnen: KU Leuven
Ragna Sannerud: VIB Center for Brain & Disease Research
Marine Bretou: VIB Center for Brain & Disease Research
Markus Damme: Christian-Albrechts-University Kiel
Wim Annaert: VIB Center for Brain & Disease Research

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-38501-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38501-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-38501-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().