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Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD.

ABSTRACT: The role of exosome-mediated mitophagy in the crosstalk between hepatocytes (HCs) and hepatic stellate cells (HSCs) in metabolic-associated fatty liver disease (MAFLD) remains unknown. Serum exosomal miR-27a levels were markedly increased and positively correlated with liver fibrosis in MAFLD patients and mice. Exosomal miR-27a was released from lipotoxic HCs and specifically transmitted to recipient-activated HSCs. PINK1, the key target of miR-27a, primarily mediates mitophagy. Overexpression of miR-27a or knockdown of PINK1 or lipotoxic HC-exosomal miR-27a impaired mitochondria (inhibiting mitophagy, respiration, membrane potential, and transcription while promoting reactive oxygen species production) in activated HSCs and stimulated HSC-derived fibroblasts (promoting activation and proliferation while inhibiting autophagy). High exosomal miR-27a serum levels and a lack of hepatic PINK1-mediated mitophagy were directly related to liver fibrosis in MAFLD mice. Lipotoxic HC exosome transplantation aggravated the degree of PINK1-mediated mitophagy suppression, steatohepatitis, lipidosis, and fibrosis in the livers of MAFLD mice with cirrhosis. Both in vitro and in vivo, exosomes derived from miR-27a-knockdown HCs could not facilitate the abovementioned deteriorating effects. In conclusion, lipotoxic HC-exosomal miR-27a plays a pivotal role in inhibiting mitophagy and in promoting MAFLD-related liver fibrosis by negatively regulating PINK1 expression.

SUBMITTER: Luo X

PROVIDER: S-EPMC8607138 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD.

Luo Xin X Xu Zi-Xin ZX Wu Jun-Cheng JC Luo Sheng-Zheng SZ Xu Ming-Yi MY

Molecular therapy. Nucleic acids 20211103

The role of exosome-mediated mitophagy in the crosstalk between hepatocytes (HCs) and hepatic stellate cells (HSCs) in metabolic-associated fatty liver disease (MAFLD) remains unknown. Serum exosomal miR-27a levels were markedly increased and positively correlated with liver fibrosis in MAFLD patients and mice. Exosomal miR-27a was released from lipotoxic HCs and specifically transmitted to recipient-activated HSCs. PINK1, the key target of miR-27a, primarily mediates mitophagy. Overexpression o ...[more]

PMID: 34853724

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Project description:Abstract backgroundRecent studies indicate that endometrial hypoxia plays a critical role in adenomyosis (AM) development. Mitochondria are extremely sensitive to hypoxic damage, which can result in both morphological and functional impairment. Mitophagy is a crucial mechanism for preserving mitochondrial quality by selectively removing damaged mitochondria, thus ensuring the proper functioning of the entire mitochondrial network. In response to hypoxia, PINK1 is activated as a regulator of mitophagy, but its role in AM requires further study.ObjectiveTo explore the potential mechanism of mitophagy mediated by PINK1 in the pathogenesis of AM.MethodThe study compared PINK1, Parkin, OPTIN, P62, and NDP52 protein expression levels in patients with or without AM using clinical specimens and an AM mouse model. Pathological changes were compared using HE staining. Immunofluorescence and western blot were used to detect protein expression levels. Endometrial stromal cells (ESC) were isolated and examined for mitophagy, protein expression level, and cell invasion ability.ResultsBoth the endometrial tissue from patients with AM and AM ESC displayed an upregulation of protein levels for PINK1, Parkin, OPTIN, P62, and NDP52 when compared with the control group. Then, HE staining confirmed the successful establishment of the AM mouse model. Moreover, the ultrastructural analysis using transmission electron microscopy revealed that AM mice's endometrial glandular epithelial and stromal cells had exhibited swollen, deformed, and reduced mitochondria along with an increase in the number of lysosomes and mitochondrial autophagosomes. The protein levels of PINK1, Parkin, OPTIN, P62, and NDP52 in uterine tissue from AM mice were noticeably increased, accompanied by a considerable upregulation of ROS levels compared to the control group. In addition, cells in the AM group showed remarkably elevated mitophagy and invasion potentials compared to the control group. In contrast, the cell invasion ability decreased following PINK1 knockdown using the RNA interference technique.ConclusionThe high levels of PINK1-mediated mitophagy have been found in AM. The upregulation in mitophagy contributes to mitochondrial damage, which may result in the abnormal invasion characteristic of AM.

Dataset Information

Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD.

Publications

Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD.

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