論文 - 詳細
| RRC ID | 85377 |
|---|---|
| 著者 | Ham SJ, Bang S, Woo D, Jo JY, Yoo T, Yoon E, Kyoung Y, Baek D, Kim JS, Chung J. |
| タイトル | Mitochondrial fumarate inhibits Parkin-mediated mitophagy. |
| ジャーナル | Mol Cell |
| Abstract |
Here, we explore the potential involvement of fumarate, a metabolite generated from the TCA cycle, as a key regulator of PINK1-Parkin-mediated mitophagy. Fumarate engages in a process called succination, forming S-(2-succino) cysteine with protein cysteine residues. Our research demonstrates that this modification specifically targets the sulfhydryl group of cysteine 323 and 451 residues of human Parkin, leading to the inhibition of its mitochondrial localization and E3 ligase activity, thereby impeding PINK1-Parkin-mediated mitophagy. Notably, our investigation reveals that the succinatable cysteines in human Parkin are not conserved in invertebrates, including Drosophila. To assess the functional impact of Parkin succination, we generate Parkin knockin flies with succinatable cysteines. These flies exhibit robust Parkinson's disease (PD)-related phenotypes when exposed to elevated fumarate levels. Collectively, our findings underscore the significance of fumarate as an endogenous regulator of PINK1-Parkin-mediated mitophagy, offering insights into the intricate interplay between mitochondrial metabolic activities and PD pathology. |
| 巻・号 | 85(12) |
| ページ | 2287-2302.e9 |
| 公開日 | 2025-6-19 |
| DOI | 10.1016/j.molcel.2025.05.021 |
| PII | S1097-2765(25)00460-5 |
| PMID | 40505663 |
| MeSH | Animals Cysteine / metabolism Drosophila Proteins* / genetics Drosophila Proteins* / metabolism Drosophila melanogaster / genetics Drosophila melanogaster / metabolism Fumarates* / metabolism Gene Knock-In Techniques Humans Mitochondria* / enzymology Mitochondria* / genetics Mitochondria* / metabolism Mitochondria* / pathology Mitophagy* Parkinson Disease* / enzymology Parkinson Disease* / genetics Parkinson Disease* / metabolism Parkinson Disease* / pathology Protein Kinases / genetics Protein Kinases / metabolism Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism Ubiquitin-Protein Ligases* / genetics Ubiquitin-Protein Ligases* / metabolism |
| IF | 15.584 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Bluesky |
| 各媒体での言及数の合計 | 22 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ショウジョウバエ | 10219R-3 6647R-1 |