Defects in PINK-PRKN-PARK7/DJ-1-dependent mitophagy and autosomal recessive Parkinson disease

Imberechts, Dorien; Vandenberghe, Wim

doi:10.1080/15548627.2022.2139129

Cited by 4 publications

(2 citation statements)

References 1 publication

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“…Impairment or loss of DJ‐1 function contributes to PD primarily through the following mechanisms: (1) Reduced interaction with the β subunit of F 1 F 0 ATP synthase, resulting in increased mitochondrial uncoupling, decreased ATP production, and hampered metabolism and growth of dopaminergic neurons (Chen, Park, et al, 2019); (2) Diminished expression of mitochondrial uncoupling proteins (UCP4 and UCP5), leading to increased mitochondrial ROS production and oxidative stress (Dolgacheva et al, 2019); (3) Inhibited recruitment of the selective autophagy receptor OPTN to depolarized mitochondria, thereby obstructing PINK1/parkin‐mediated mitophagy (Imberechts et al, 2022). Notably, skin fibroblasts and iPSC‐derived neurons from a PD patient harboring a homozygous PARK7 mutation exhibit severe impairment in PINK/Parkin‐mediated mitophagy, comparable in magnitude to that observed in cells from PD patients with PINK1 or PRKN mutations (Imberechts & Vandenberghe, 2023). Interestingly, the overexpression of DJ‐1 cannot restore mitophagy in PINK1‐ or parkin‐deficient cells, implying that DJ‐1 acts as a downstream mediator in PINK1/Parkin‐dependent mitophagy (Imberechts et al, 2022).…”

Section: Pd‐related Proteins Associated With Mitophagy and Mitochondr...mentioning

confidence: 82%

Regulation of mitophagy and mitochondrial function: Natural compounds as potential therapeutic strategies for Parkinson's disease

Liang,

Ma,

Zhong

et al. 2024

Phytotherapy Research

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Mitochondrial damage is associated with the development of Parkinson's disease (PD), indicating that mitochondrial‐targeted treatments could hold promise as disease‐modifying approaches for PD. Notably, natural compounds have demonstrated the ability to modulate mitochondrial‐related processes. In this review article, we discussed the possible neuroprotective mechanisms of natural compounds against PD in modulating mitophagy and mitochondrial function. A comprehensive literature search on natural compounds related to the treatment of PD by regulating mitophagy and mitochondrial function was conducted from PubMed, Web of Science and Chinese National Knowledge Infrastructure databases from their inception until April 2023. We summarize recent advancements in mitophagy's molecular mechanisms, including upstream and downstream processes, and its relationship with PD‐related genes or proteins. Importantly, we highlight how natural compounds can therapeutically regulate various mitochondrial processes through multiple targets and pathways to alleviate oxidative stress, neuroinflammation, Lewy's body aggregation and apoptosis, which are key contributors to PD pathogenesis. Unlike the single‐target strategy of modern medicine, natural compounds provide neuroprotection against PD by modulating various mitochondrial‐related processes, including ameliorating mitophagy by targeting the PINK1/parkin pathway, the NIX/BNIP3 pathway, and autophagosome formation (i.e., LC3 and p62). Given the prevalence of mitochondrial damage in various neurodegenerative diseases, exploring the exact mechanism of natural compounds on mitophagy and mitochondrial dysfunction could shed light on the development of highly effective disease‐modifying or adjuvant therapies targeting PD and other neurodegenerative disorders.

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Section: Pd‐related Proteins Associated With Mitophagy and Mitochondr...mentioning

confidence: 82%

Regulation of mitophagy and mitochondrial function: Natural compounds as potential therapeutic strategies for Parkinson's disease

Liang,

Ma,

Zhong

et al. 2024

Phytotherapy Research

View full text Add to dashboard Cite

show abstract

“…Among the identified histidine sites, PARK7, also called DJ1, is a protein that plays a role in protecting cells from oxidative stress and acts as an essential downstream mediator in PINK1/parkin-dependent mitophagy 59 . Mutations in PARK7 has been reported to disrupt the mitophagy, leading to the accumulation of damaged mitochondria and the eventual death of dopaminergic neurons 60 .…”

Section: Discovery Of Novel Histidine Functions In Metalloproteinsmentioning

confidence: 99%

Global profiling of functional histidines in live cells using small molecule photosensitizer and chemical probe relay labeling

Zhai,

Zhang,

Yan

et al. 2023

Preprint

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Recent advances in chemical proteomics have focused on developing chemical probes reacting with nucleophilic amino acid residues throughout the proteome. Among the nucleophilic amino acids, histidine is an attractive candidate due to its presence in enzyme active sites, metal-binding sites, and protein-protein interaction interfaces. However, histidine has moderate nucleophilicity, and its modification is easily influenced by cysteine and lysine, resulting in poor selectivity and narrow proteome coverage. Here, we report a singlet oxygen and chemical probe relay labeling method that achieves exquisite selectivity towards histidine. A small molecular photosensitizer library is screened together with a chemical probe library to optimize the histidine labeling, enabling histidine profiling in live cells with over 7500 unique sites. We applied this method to discover unannotated histidine sites for metalloproteins and characterize the key histidine residues H309 for metabolic enzyme IDH1 and H73 for CRIP1. Finally, we used this method to probe the accessibility of histidine residues in mitophagy, revealing H138 of PARK7 as the key residue influencing the protein subcellular localization and stability. These findings demonstrate the applicability of our method in discovering functional histidine sites in the human proteome.

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GPR50 regulates neuronal development as a mitophagy receptor

Liu,

Zhao,

et al. 2024

Cell Death Dis

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Neurons rely heavily on high mitochondrial metabolism to provide sufficient energy for proper development. However, it remains unclear how neurons maintain high oxidative phosphorylation (OXPHOS) during development. Mitophagy plays a pivotal role in maintaining mitochondrial quality and quantity. We herein describe that G protein-coupled receptor 50 (GPR50) is a novel mitophagy receptor, which harbors the LC3-interacting region (LIR) and is required in mitophagy under stress conditions. Although it does not localize in mitochondria under normal culturing conditions, GPR50 is recruited to the depolarized mitochondrial membrane upon mitophagy stress, which marks the mitochondrial portion and recruits the assembling autophagosomes, eventually facilitating the mitochondrial fragments to be engulfed by the autophagosomes. Mutations Δ502-505 and T532A attenuate GPR50-mediated mitophagy by disrupting the binding of GPR50 to LC3 and the mitochondrial recruitment of GPR50. Deficiency of GPR50 causes the accumulation of damaged mitochondria and disrupts OXPHOS, resulting in insufficient ATP production and excessive ROS generation, eventually impairing neuronal development. GPR50-deficient mice exhibit impaired social recognition, which is rescued by prenatal treatment with mitoQ, a mitochondrially antioxidant. The present study identifies GPR50 as a novel mitophagy receptor that is required to maintain mitochondrial OXPHOS in developing neurons.

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Defects in PINK-PRKN-PARK7/DJ-1-dependent mitophagy and autosomal recessive Parkinson disease

Cited by 4 publications

References 1 publication

Regulation of mitophagy and mitochondrial function: Natural compounds as potential therapeutic strategies for Parkinson's disease

Regulation of mitophagy and mitochondrial function: Natural compounds as potential therapeutic strategies for Parkinson's disease

Global profiling of functional histidines in live cells using small molecule photosensitizer and chemical probe relay labeling

GPR50 regulates neuronal development as a mitophagy receptor

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