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

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

doi:10.1038/s41467-023-38501-w

Cited by 33 publications

(8 citation statements)

References 111 publications

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“…L308P of hPLD3 has been genetically associated with SCA, and its 5¢-exonuclease activity was found to be impaired [47,48]. In a recent paper, it was suggested that PLD3 can degrade mitochondrial DNA to block cGAS/STING activation and thereby possibly prevent neurodegenerative diseases [49,50]. For PLD4, several disease-associated mutants have been reported in the Genome Aggregation Database (gnomAD) [51] (Figure S6).…”

Section: Resultsmentioning

confidence: 99%

Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4

Yuan,

Peng,

Huang

et al. 2023

Preprint

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Endolysosomal exonucleases PLD3 and PLD4 (phospholipases D3 and D4) are associated with autoinflammatory and autoimmune diseases. We report structures of these enzymes, and the molecular basis of their catalysis. The structures reveal an intra-chain dimer topology forming a basic active site at the interface. Like other PLD superfamily members, PLD3 and PLD4 carry HxKxxxxD/E motifs and participate in phosphodiester-bond cleavage. The enzymes digest ssDNA and ssRNA in a 5′-to-3′ manner and are blocked by 5′-phosphorylation. We captured structures in apo, intermediate, and product states and revealed a ‘link-and-release’ two-step catalysis. We also unexpectedly demonstrated phosphatase activity via a covalent 3’- phosphistidine intermediate. PLD4 contains an extra hydrophobic clamp that stabilizes substrate and could affect oligonucleotide substrate preference and product release. Biochemical and structural analysis of disease-associated mutants of PLD3/4 demonstrated reduced enzyme activity or thermostability and the possible basis for disease association. Furthermore, these findings provide insight into therapeutic design.

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Section: Resultsmentioning

confidence: 99%

Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4

Yuan,

Peng,

Huang

et al. 2023

Preprint

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“…It is possible that dcNUMTs are transcribed and may have a function on the RNA level, or that the DNA itself has some regulatory function as observed for mitochondrial DNA (Acker et al 2023) or creates novel exons (Noutsos et al 2007). For example, the transcription of non-coding genomic DNA is very common (Gao et al 2020) and active retroviruses (Bolisetty et al 2012) may could lead to expression of NUMTs as well.…”

Section: Discussionmentioning

confidence: 99%

Phylonumtomics uncovers diverse evolutionary trajectories of mitogenomic fossils buried in mammalian and avian genomes

Chen,

Vendrami,

Huber

et al. 2023

Preprint

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Sporadically genetic material that originates from an organelle genome integrates into the nuclear genome. However it is unclear what processes maintain such an integration over longer evolutionary time. Recently it was shown that nuclear DNA of mitochondrial origin (NUMTs) may harbour genes with intact mitochondrial reading frames despite the fact that they are highly divergent to the host's mitochondrial genome. Two major hypotheses have been put forward to explain the existence of such mitocoding nuclear genes: (A) recent introgression from another species and (B) long-term selection. To address whether these intriguing possibilities do play a role we scanned the genomes of more than 1,000 avian and mammalian species for NUMTs. We indeed identified that the subclass of divergent NUMTs harbouring mitogenes with intact reading frames are widespread across mammals and birds. We can show that for these NUMTs signatures of cross-species introgression are widespread in birds, but not mammals with the exception of ungulates. We can also show that a substantial fraction of deeply divergent NUMTs are maintained by selection. For a small number of NUMT genes we identify an evolutionary signature that is consistent with adaptive evolution including one human NUMT that is shared among seven ape species. This highlights the intriguing possibility that NUMT insertions occasionally may be functional.

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“…37 Moreover, altering the activity of phospholipase D3, a risk gene of late-onset AD, significantly impacted APP processing and cholesterol metabolism. 39…”

Section: Cholesterol Homeostasis and Apoe In Admentioning

confidence: 99%

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

Wang,

Zhen,

Yang

et al. 2024

CNS Neurosci Ther

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BackgroundAccumulation of amyloid beta, tau hyperphosphorylation, and microglia activation are the three highly acknowledged pathological factors of Alzheimer's disease (AD). However, oligodendrocytes (OLs) were also widely investigated in the pathogenesis and treatment for AD.AimsWe aimed to update the regulatory targets of the differentiation and maturation of OLs, and emphasized the key role of OLs in the occurrence and treatment of AD.MethodsThis review first concluded the targets of OL differentiation and maturation with AD pathogenesis, and then advanced the key role of OLs in the pathogenesis of AD based on both clinic and basic experiments. Later, we extensively discussed the possible application of the current progress in the diagnosis and treatment of this complex disease.ResultsMolecules involving in OLs’ differentiation or maturation, including various transcriptional factors, cholesterol homeostasis regulators, and microRNAs could also participate in the pathogenesis of AD. Clinical data point towards the impairment of OLs in AD patients. Basic research further supports the central role of OLs in the regulation of AD pathologies. Additionally, classic drugs, including donepezil, edaravone, fluoxetine, and clemastine demonstrate their potential in remedying OL impairment in AD models, and new therapeutics from the perspective of OLs is constantly being developed.ConclusionsWe believe that OL dysfunction is one important pathogenesis of AD. Factors regulating OLs might be biomarkers for early diagnosis and agents stimulating OLs warrant the development of anti‐AD drugs.

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

Cited by 33 publications

References 111 publications

Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4

Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4

Phylonumtomics uncovers diverse evolutionary trajectories of mitogenomic fossils buried in mammalian and avian genomes

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

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