Preserving mitochondrial homeostasis protects against drug-induced liver injury via inducing OPTN (optineurin)-dependent Mitophagy.

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.