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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Inhibition of mitoNEET induces Pink1-Parkin-mediated mitophagy

  • Lee, Seunghee (School of Biological Sciences, College of Natural Sciences, University of Ulsan) ;
  • Lee, Sangguk (School of Biological Sciences, College of Natural Sciences, University of Ulsan) ;
  • Lee, Seon-Jin (Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Chung, Su Wol (School of Biological Sciences, College of Natural Sciences, University of Ulsan)
  • Received : 2022.03.02
  • Accepted : 2022.05.10
  • Published : 2022.07.31
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Abstract

MitoNEET, a mitochondrial outer membrane protein containing the Asn-Glu-Glu-Thr (NEET) sequence, controls the formation of intermitochondrial junctions and confers autophagy resistance. Moreover, mitoNEET as a mitochondrial substrate undergoes ubiquitination by activated Parkin during the initiation of mitophagy. Therefore, mitoNEET is linked to the regulation of autophagy and mitophagy. Mitophagy is the selective removal of the damaged or unnecessary mitochondria, which is crucial to sustaining mitochondrial quality control. In numerous human diseases, the accumulation of damaged mitochondria by impaired mitophagy has been observed. However, the therapeutic strategy targeting of mitoNEET as a mitophagy-enhancing mediator requires further research. Herein, we confirmed that mitophagy is indeed activated by mitoNEET inhibition. CCCP (carbonyl cyanide m-chlorophenyl hydrazone), which leads to mitochondrial depolarization, induces mitochondrial dysfunction and superoxide production. This, in turn, contributes to the induction of mitophagy; mitoNEET protein levels were initially increased before an increase in LC3-II protein following CCCP treatment. Pharmacological inhibition of mitoNEET using mitoNEET Ligand-1 (NL-1) promoted accumulation of Pink1 and Parkin, which are mitophagy-associated proteins, and activation of mitochondria-lysosome crosstalk, in comparison to CCCP alone. Inhibition of mitoNEET using NL-1, or mitoNEET shRNA transfected into RAW264.7 cells, abrogated CCCP-induced ROS and mitochondrial cell death; additionally, it activated the expression of PGC-1α and SOD2, regulators of oxidative metabolism. In particular, the increase in PGC-1α, which is a major regulator of mitochondrial biogenesis, promotes mitochondrial quality control. These results indicated that mitoNEET is a potential therapeutic target in numerous human diseases to enhance mitophagy and protect cells by maintaining a network of healthy mitochondria.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education to S.W.C. (NRF-2014R1A6A1030318 and NRF-2021R1A2C1094382) and the KRIBB and KIST institutional Program to S.J.L. (KGM5322214 and 2E31700-22-P005).

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