2. Academic Validation
  3. Mitochondrial fumarate inhibits Parkin-mediated mitophagy

Mitochondrial fumarate inhibits Parkin-mediated mitophagy

  • Mol Cell. 2025 Jun 19;85(12):2287-2302.e9. doi: 10.1016/j.molcel.2025.05.021.
Su Jin Ham 1,  Sunhoe Bang 1,  Daihn Woo 2,  Jae-Yoon Jo 3,  Takwon Yoo 4,  Eunju Yoon 1,  Yeonju Kyoung 3,  Daehyun Baek 1,  Jong-Seo Kim 5,  Jongkyeong Chung 6
Affiliations

Affiliations

  • 1 Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Republic of Korea; School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Republic of Korea.
  • 3 School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea; Center for RNA Research, Institute for Basic Science, Seoul 08826, Republic of Korea.
  • 4 School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • 5 School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea; Center for RNA Research, Institute for Basic Science, Seoul 08826, Republic of Korea. Electronic address: jongseokim@snu.ac.kr.
  • 6 Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Republic of Korea; School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea; Apt Neuroscience Inc., Gyeonggi-do 13215, Republic of Korea. Electronic address: jkc@snu.ac.kr.
PMID: 40505663 DOI: 10.1016/j.molcel.2025.05.021
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.

Keywords

ANT1; PINK1; Parkinson's disease; VDAC1/2; fumarate; parkin; succination.

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