ABSTRACT
Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs.
Abbreviation: AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic – pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2.
Acknowledgements
We thank Prof. Ronggui Hu for gifted optn−/− mice and OPTN related plasmids and Prof. Xiangnan Zhang for gifted mitoQC plasmid. We thank Bowen Peng, Hongbo Ma, Chunxiao Shao, Shipeng Song, and Jingmei Zhou for collecting and analyzing data for revision.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data and materials availability
The RNA-seq data of optn−/− and WT livers upon APAP treatment are deposited in the NCBI Gene Expression Omnibus (GEO) under accession number: GSE195753. The gene expression datasets for the injured and healthy human livers are extracted from GSE74000, GSE38941, GSE46995, GSE28619, and GSE63068. Six DILI datasets and five chronic liver disease datasets are extracted from GSE17649 (APAP), GSE102150 (Monocrotaline), GSE55489 (INH), GSE136059 (Idelalisib), GSE93840 (Amiodarone), GSE75277 (Diclofenac), GSE28619 (Alcoholic Hepatitis), GSE25097 (cirrhosis), GSE48452 (Steatosis and NASH), GSE63068 (NAFLD).
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2024.2384348