Journal article
G protein β5-ATM complexes drive acetaminophen-induced hepatotoxicity
Redox biology, Vol.43, pp.101965-101965
07/01/2021
DOI: 10.1016/j.redox.2021.101965
PMCID: PMC8105674
PMID: 33933881
Abstract
Excessive ingestion of the common analgesic acetaminophen (APAP) leads to severe hepatotoxicity. Here we identify G protein β5 (Gβ5), elevated in livers from APAP overdose patients, as a critical regulator of cell death pathways and autophagic signaling in APAP-exposed liver. Liver-specific knockdown of Gβ5 in mice protected the liver from APAP-dependent fibrosis, cell loss, oxidative stress, and inflammation following either acute or chronic APAP administration. Conversely, overexpression of Gβ5 in liver was sufficient to drive hepatocyte dysfunction and loss. In hepatocytes, Gβ5 depletion ameliorated mitochondrial dysfunction, allowed for maintenance of ATP generation and mitigated APAP-induced cell death. Further, Gβ5 knockdown also reversed impacts of APAP on kinase cascades (e.g. ATM/AMPK) signaling to mammalian target of rapamycin (mTOR), a master regulator of autophagy and, as a result, interrupted autophagic flux. Though canonically relegated to nuclear DNA repair pathways, ATM also functions in the cytoplasm to control cell death and autophagy. Indeed, we now show that Gβ5 forms a direct, stable complex with the FAT domain of ATM, important for autophosphorylation-dependent kinase activation. These data provide a viable explanation for these novel, G protein-independent actions of Gβ5 in liver. Thus, Gβ5 sits at a critical nexus in multiple pathological sequelae driving APAP-dependent liver damage.
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•Gβ5 is robustly up-regulated in livers from human patients with a history of chronic APAP use.•Gβ5is both necessary and sufficient for APAP-dependent oxidative stress and cell loss in liver.•Gβ5 knockdown allows for maintenance of hepatic function, decreases fibrosis and inflammation, and mitigates lethality following APAP exposure.•Gβ5 forms a direct complex with ATM to drive ROS generation and trigger cell death.
Details
- Title: Subtitle
- G protein β5-ATM complexes drive acetaminophen-induced hepatotoxicity
- Creators
- Arnab Pramanick - Sanjay Gandhi Post Graduate Institute of Medical SciencesSreemoyee Chakraborti - Sanjay Gandhi Post Graduate Institute of Medical SciencesTarun Mahata - Centre of Biomedical ResearchMadhuri Basak - Centre of Biomedical ResearchKiran Das - Centre of Biomedical ResearchSumit Kumar Verma - Sanjay Gandhi Post Graduate Institute of Medical SciencesAbhishek Singh Sengar - Sanjay Gandhi Post Graduate Institute of Medical SciencesPraveen Kumar Singh - University of MiamiPranesh Kumar - Babasaheb Bhimrao Ambedkar UniversityBolay Bhattacharya - Department of Pharmacy, Geethanjali College of Pharmacy, Cheeryala, Keesara(M), Rangareddy District, Telangana, 501301, IndiaSayan Biswas - College of Medicine & Sagore Dutta HospitalParag Baran Pal - College of Medicine & Sagore Dutta HospitalSubhasish Sarkar - College of Medicine & Sagore Dutta HospitalVinita Agrawal - Sanjay Gandhi Post Graduate Institute of Medical SciencesSudipta Saha - Babasaheb Bhimrao Ambedkar UniversityDebjani Nath - University of KalyaniSuvro Chatterjee - Anna University, ChennaiAdele Stewart - Florida Atlantic UniversityBiswanath Maity - Centre of Biomedical Research
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.43, pp.101965-101965
- Publisher
- Elsevier B.V
- DOI
- 10.1016/j.redox.2021.101965
- PMID
- 33933881
- PMCID
- PMC8105674
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Grant note
- DOI: 10.13039/501100001407, name: Department of Biotechnology
- Language
- English
- Date published
- 07/01/2021
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618509202771
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