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LC-MS Dataset of Fumarate Levels and Parkin Post Translational Modifications

ABSTRACT: This study investigates the regulatory role of fumarate, a metabolite of the citric acid cycle, in PINK1-Parkin-mediated mitophagy-a process essential for mitochondrial quality control and implicated in Parkinsons disease (PD). We identified post-translational succination modifications on Parkin at cysteine residues 323 and 451, demonstrating that fumarate-mediated succination impairs Parkins mitochondrial localization and E3 ligase activity. Using proteomic LC-MS, we discovered novel succination sites, while metabolomic LC-MS enabled the quantification of fumarate levels in biological samples, including mammalian cells and Drosophila. Functional validation with Parkin knock-in Drosophila models harboring succinatable cysteines revealed PD-like phenotypes upon fumarate accumulation, underscoring the physiological relevance of this modification. Our integrated proteomic and metabolomic approach establishes fumarate as an endogenous modulator of mitophagy and provides new insights into the role of mitochondrial metabolism in PD pathogenesis.

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion Lumos

ORGANISM(S): Drosophila Melanogaster (ncbitaxon:7227) Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Jong-Seo Kim

PROVIDER: MSV000097910 | MassIVE | Mon May 19 17:23:00 BST 2025

REPOSITORIES: MassIVE

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Project description:This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PTEN-induced putative kinase 1 (PINK1)-Parkin mediated mitophagy, NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation, and apoptosis. We found that recombinant DEK protein (rmDEK) promoted eosinophils recruitment, mitochondrial fragmentation, and outer membrane 20 (TOM20) and LC3 co-localization representing mitophagosomes in bronchoalveolar lavage fluid (BALF) in house dust mite (HDM) induced-asthma. rmDEK also reduced co-localization of mitochondrial fusion protein mitofusin1 (MFN1) and mitochondria, and the protein level of manganese superoxide dismutase (MnSOD), enhanced microtubule-associated protein1 light chain 3 (LC3) and voltage-dependent anion channels (VDAC) co-localization which also represent the mitophagosomes in airway epithelial cells, furthermore, increased dynamin-related protein 1 (DRP1) expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. In the DEK knockout mice, HDM induced asthmatic airway inflammation, MnSOD, PINK1-Parkin protein level, Parkin mediated mitophagy characterized by LC3 and Parkin co-localization in the airways, ROS generation, NLRP3 inflammation and apoptosis were fully reversed. Similar effects of rmDEK were also observed in the BEAS-2B cells, which were rescued by the autophagy inhibitor 3-MA. Moreover, DEK silencing diminished the Parkin, LC3, DRP1 translocation to mitochondria; as well as mitochondrial ROS; TOM20 and mitochondrial DNA mediated mitochondrial oxidative damage. ChIP-sequence analysis showed that DEK was enriched on the AAA domain-containing protein 3A (ATAD3A) promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models. Furthermore, ATAD3A interacted with DRP1, and knockdown of ATAD3A could down-regulate DRP1 and mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.

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LC-MS Dataset of Fumarate Levels and Parkin Post Translational Modifications

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