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Inhibition of mitoNEET induces Pink1-Parkin-mediated mitophagy
Seunghee Lee 1 (Research worker), Sangguk Lee 1 (Graduate student), Seon-Jin Lee 2 (Doctor), Su Wol Chung 1,* (Professor)
1School of Biological Sciences, College of Natural Sciences, University of Ulsan, 93 Daehak-ro, Nam-gu, Ulsan 44610, South Korea,
2Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, 305–806, South Korea
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 in the initiation of mitophagy. Therefore, mitoNEET is linked to the regulation of autophagy and mitophagy. Mitophagy is a selective removal process of 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. The therapeutic strategy involving the 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 the increase in LC3-ケ 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, as well as 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-1メ and SOD2, regulators of oxidative metabolism. In particular, the increase in PGC-1メ, which is a major regulator of mitochondrial biogenesis, promotes mitochondrial quality control. These data indicated that mitoNEET may be employed as a therapeutic target in numerous human diseases to enhance mitophagy and protect cells by maintaining a network of healthy mitochondria.
Abstract, Accepted Manuscript(in press) [Submitted on March 2, 2022, Accepted on May 10, 2022]
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