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Mitochondrial Ca²⁺ oscillation induces mitophagy initiation through the PINK1-Parkin pathway.

ABSTRACT: Dysregulation of the PINK1/Parkin-mediated mitophagy is essential to Parkinson's disease. Although important progress has been made in previous researches, the biochemical reagents that induce global and significant mitochondrial damage may still hinder deeper insights into the mechanisms of mitophagy. The origin of PINK1/Parkin pathway activation in mitophagy remains elusive. In this study, we develop an optical method, ultra-precise laser stimulation (UPLaS) that delivers a precise and noninvasive stimulation onto a submicron region in a single mitochondrial tubular structure. UPLaS excites localized mitochondrial Ca²⁺ (mitoCa²⁺) oscillations with tiny perturbation to mitochondrial membrane potential (MMP) or mitochondrial reactive oxygen species. The UPLaS-induced mitoCa²⁺ oscillations can directly induce PINK1 accumulation and Parkin recruitment on mitochondria. The Parkin recruitment by UPLaS requires PINK1. Our results provide a precise and noninvasive technology for research on mitophagy, which stimulates target mitochondria with little damage, and reveal mitoCa²⁺ oscillation directly initiates the PINK1-Parkin pathway for mitophagy without MMP depolarization.

SUBMITTER: Yu Z

PROVIDER: S-EPMC8214625 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Mitochondrial Ca<sup>2+</sup> oscillation induces mitophagy initiation through the PINK1-Parkin pathway.

Yu Zhengying Z Wang Haipeng H Tang Wanyi W Wang Shaoyang S Tian Xiaoying X Zhu Yujie Y He Hao H

Cell death & disease 20210619 7

Dysregulation of the PINK1/Parkin-mediated mitophagy is essential to Parkinson's disease. Although important progress has been made in previous researches, the biochemical reagents that induce global and significant mitochondrial damage may still hinder deeper insights into the mechanisms of mitophagy. The origin of PINK1/Parkin pathway activation in mitophagy remains elusive. In this study, we develop an optical method, ultra-precise laser stimulation (UPLaS) that delivers a precise and noninva ...[more]

PMID: 34148057

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Project description: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. [BMB Reports 2022; 55(7): 354-359].

Dataset Information

Mitochondrial Ca²⁺ oscillation induces mitophagy initiation through the PINK1-Parkin pathway.

Publications

Mitochondrial Ca<sup>2+</sup> oscillation induces mitophagy initiation through the PINK1-Parkin pathway.

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Dataset Information

Mitochondrial Ca2+ oscillation induces mitophagy initiation through the PINK1-Parkin pathway.

Publications

Mitochondrial Ca<sup>2+</sup> oscillation induces mitophagy initiation through the PINK1-Parkin pathway.

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OmicsDI is part of the ELIXIR infrastructure

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Mitochondrial Ca²⁺ oscillation induces mitophagy initiation through the PINK1-Parkin pathway.