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

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 24, 2023

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.

Language: Английский

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Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson’s disease

Science Advances, Journal Year: 2023, Volume and Issue: 9(29)

Published: July 19, 2023

Mutations in the E3 ubiquitin ligase parkin are most common cause of early-onset Parkinson's disease (PD). Although modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether regulates lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway iPSC-derived dopaminergic neurons from patients with PD. Compared to isogenic controls, mutant exhibit decreased mitochondria-lysosome contacts via destabilization active Rab7. Subcellular reveals accumulation lysosomes their deficiency mitochondria. Knockdown Rab7 GTPase-activating protein TBC1D15 restores tethering ameliorates subcellular profiles neurons. Our data thus uncover function promoting through stabilization suggest that modulation interorganelle may serve potential target for ameliorating dyshomeostasis disease.

Language: Английский

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Key genes and convergent pathogenic mechanisms in Parkinson disease

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(6), P. 393 - 413

Published: April 10, 2024

Language: Английский

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Cell biology of Parkinson's disease: Mechanisms of synaptic, lysosomal, and mitochondrial dysfunction

Current Opinion in Neurobiology, Journal Year: 2024, Volume and Issue: 85, P. 102841 - 102841

Published: Feb. 1, 2024

Language: Английский

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Glucocerebrosidase-associated Parkinson disease: Pathogenic mechanisms and potential drug treatments

Neurobiology of Disease, Journal Year: 2022, Volume and Issue: 166, P. 105663 - 105663

Published: Feb. 17, 2022

Dysfunction of the endolysosomal system is implicated in pathogenesis both sporadic and familial Parkinson disease (PD). Variants genes encoding lysosomal proteins have been estimated to be associated with more than half PD cases. The most common genetic risk factor for are variants GBA gene, enzyme glucocerebrosidase (GCase), which involved sphingolipid metabolism. In this review we will describe clinical symptoms pathology GBA-PD, how might affected by type variant. putative mechanisms GCase deficiency neurons glia contribute then discussed, particular emphasis on accumulation α-synuclein aggregates spread pathogenic species between cell types. dysregulation not only sphingolipids, but also phospholipids cholesterol misfolding reviewed, as neuroinflammation interaction LRRK2 protein, another important contributor pathogenesis. Study non-manifesting carriers GBA-PD cohorts provides an opportunity identify robust biomarkers progression well trials potential treatments. final part preclinical studies increasing activity or reducing toxic substrate accumulation.

Language: Английский

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Dysregulation of organelle membrane contact sites in neurological diseases

Neuron, Journal Year: 2022, Volume and Issue: 110(15), P. 2386 - 2408

Published: May 12, 2022

Language: Английский

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Oxidative stress and synaptic dysfunction in rodent models of Parkinson's disease

Neurobiology of Disease, Journal Year: 2022, Volume and Issue: 173, P. 105851 - 105851

Published: Aug. 23, 2022

Parkinson's disease (PD) is a multifactorial disorder involving complex interplay between variety of genetic and environmental factors. In this scenario, mitochondrial impairment oxidative stress are widely accepted as crucial neuropathogenic mechanisms, also evidenced by the identification PD-associated genes that directly involved in function. The concept dysfunction closely linked to synaptic dysfunction. Indeed, compelling evidence supports role mitochondria transmission plasticity, although many aspects have not yet been fully elucidated. Here, we will provide brief overview most relevant obtained different neurotoxin-based rodent models PD, focusing on synaptopathy, an early central event preceding overt nigrostriatal neurodegeneration. deficits occurring PD pathogenesis view development potential disease-modifying therapeutic strategies.

Language: Английский

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Arf1 coordinates fatty acid metabolism and mitochondrial homeostasis

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(8), P. 1157 - 1172

Published: July 3, 2023

Lipid mobilization through fatty acid β-oxidation is a central process essential for energy production during nutrient shortage. In yeast, this catabolic starts in the peroxisome from where products enter mitochondria and fuel tricarboxylic cycle. Little known about physical metabolic cooperation between these organelles. Here we found that expression of transporters rate-limiting enzyme involved decreased cells expressing hyperactive mutant small GTPase Arf1, leading to an accumulation acids lipid droplets. Consequently, became fragmented ATP synthesis decreased. Genetic pharmacological depletion phenocopied arf1 mitochondrial phenotype. Although occurs both peroxisomes mammals, Arf1's role metabolism conserved. Together, our results indicate Arf1 integrates into by regulating storage utilization, presumably organelle contact sites.

Language: Английский

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Catalytic Bioswitch of Platinum Nanozymes: Mechanistic Insights of Reactive Oxygen Species Scavenging in the Neurovascular Unit

Nano Letters, Journal Year: 2023, Volume and Issue: 23(10), P. 4660 - 4668

Published: May 8, 2023

Oxidative stress is known to be the cause of several neurovascular diseases, including neurodegenerative disorders, since increase reactive oxygen species (ROS) levels can lead cellular damage, blood-brain barrier leaking, and inflammatory pathways. Herein, we demonstrate therapeutic potential 5 nm platinum nanoparticles (PtNPs) effectively scavenge ROS in different models unit. We investigated mechanism underlying PtNP biological activities, analyzing influence evolving environment during particle trafficking disclosing a key role protein corona, which elicited an effective switch-off catalytic properties, promoting their selective

Language: Английский

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Revealing Mitochondrion–Lysosome Dynamic Interactions and pH Variations in Live Cells with a pH-Sensitive Fluorescent Probe

Analytical Chemistry, Journal Year: 2023, Volume and Issue: 95(45), P. 16609 - 16617

Published: Nov. 2, 2023

Mitochondrion–lysosome interactions have garnered significant attention in recent research. Numerous studies shown that mitochondrion–lysosome interactions, including contact (MLC) and mitophagy, are involved various biological processes pathological conditions. Single fluorescent probes termed a pivotal chemical tool unraveling the intricate spatiotemporal interorganelle interplay live cells. However, current tools insufficient to deeply understand dynamic related diseases, Moreover, rational design of dual-targeting is intractable. Herein, we designed synthesized pH-sensitive probe called INSA, which could simultaneously light up mitochondria (red emission) lysosomes (green for their internal pH differences. Employing successfully recorded long-term between mitochondria. More importantly, increasing ferroptotic cells were also revealed by INSA. Further, observed variations during ferroptosis first time. In brief, this work not only introduced INSA disclosure interplays but pioneered visualization organellar alternation specific disease model.

Language: Английский

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