PMID- 33933881
OWN - NLM
STAT- MEDLINE
DCOM- 20210705
LR  - 20210705
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 43
DP  - 2021 Jul
TI  - G protein beta5-ATM complexes drive acetaminophen-induced hepatotoxicity.
PG  - 101965
LID - S2213-2317(21)00113-0 [pii]
LID - 10.1016/j.redox.2021.101965 [doi]
LID - 101965
AB  - Excessive ingestion of the common analgesic acetaminophen (APAP) leads to severe 
      hepatotoxicity. Here we identify G protein beta5 (Gbeta(5)), 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 Gbeta(5) 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 Gbeta(5) in liver was sufficient to drive hepatocyte 
      dysfunction and loss. In hepatocytes, Gbeta(5) depletion ameliorated mitochondrial 
      dysfunction, allowed for maintenance of ATP generation and mitigated APAP-induced 
      cell death. Further, Gbeta(5) 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 
      Gbeta(5) 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 Gbeta(5) in liver. 
      Thus, Gbeta(5) sits at a critical nexus in multiple pathological sequelae driving 
      APAP-dependent liver damage.
CI  - Copyright (c) 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Pramanick, Arnab
AU  - Pramanick A
AD  - Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical 
      Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.
FAU - Chakraborti, Sreemoyee
AU  - Chakraborti S
AD  - Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical 
      Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.
FAU - Mahata, Tarun
AU  - Mahata T
AD  - Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical 
      Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.
FAU - Basak, Madhuri
AU  - Basak M
AD  - Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical 
      Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.
FAU - Das, Kiran
AU  - Das K
AD  - Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical 
      Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.
FAU - Verma, Sumit Kumar
AU  - Verma SK
AD  - Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical 
      Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.
FAU - Sengar, Abhishek Singh
AU  - Sengar AS
AD  - Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical 
      Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.
FAU - Singh, Praveen Kumar
AU  - Singh PK
AD  - Department of Surgery, Millers School of Medicine, University of Miami, Miami, 
      FL, 33136, USA.
FAU - Kumar, Pranesh
AU  - Kumar P
AD  - Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, 
      Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India.
FAU - Bhattacharya, Bolay
AU  - Bhattacharya B
AD  - Department of Pharmacy, Geethanjali College of Pharmacy, Cheeryala, Keesara(M), 
      Rangareddy District, Telangana, 501301, India.
FAU - Biswas, Sayan
AU  - Biswas S
AD  - Department of Forensic Medicine, College of Medicine and Sagore Dutta Hospital, 
      B.T. Road, Kamarhati, Kolkata, West Bengal, 700058, India.
FAU - Pal, Parag Baran
AU  - Pal PB
AD  - Department of Forensic Medicine, College of Medicine and Sagore Dutta Hospital, 
      B.T. Road, Kamarhati, Kolkata, West Bengal, 700058, India.
FAU - Sarkar, Subhasish
AU  - Sarkar S
AD  - Department of Surgery, College of Medicine and Sagore Dutta Hospital, B.T. Road, 
      Kamarhati, Kolkata, West Bengal, 700058, India.
FAU - Agrawal, Vinita
AU  - Agrawal V
AD  - Department of Pathology, Sanjay Gandhi Post-Graduate Institute of Medical 
      Sciences (SGPGIMS), Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.
FAU - Saha, Sudipta
AU  - Saha S
AD  - Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, 
      Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India.
FAU - Nath, Debjani
AU  - Nath D
AD  - Department of Zoology, University of Kalyani, Nadia, West Bengal, 741235, India.
FAU - Chatterjee, Suvro
AU  - Chatterjee S
AD  - Department of Biotechnology, Anna University and Vascular Biology Laboratory, 
      AU-KBC Research Centre, MIT Campus, Chennai, 600044, India.
FAU - Stewart, Adele
AU  - Stewart A
AD  - Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida 
      Atlantic University, Jupiter, FL, 33458, USA.
FAU - Maity, Biswanath
AU  - Maity B
AD  - Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical 
      Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India. 
      Electronic address: bmaity@cbmr.res.in.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210428
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 362O9ITL9D (Acetaminophen)
RN  - EC 2.7.11.1 (ATM protein, human)
RN  - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
SB  - IM
MH  - *Acetaminophen
MH  - Animals
MH  - Ataxia Telangiectasia Mutated Proteins/metabolism
MH  - *Chemical and Drug Induced Liver Injury/metabolism
MH  - GTP-Binding Proteins/metabolism
MH  - Hepatocytes
MH  - Humans
MH  - Liver/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Oxidative Stress
PMC - PMC8105674
OTO - NOTNLM
OT  - ATM
OT  - Acetaminophen
OT  - Autophagy
OT  - Drug-induced liver injury
OT  - G protein beta5
OT  - Oxidative stress
COIS- The authors declare no conflicts of interest.
EDAT- 2021/05/03 06:00
MHDA- 2021/07/06 06:00
PMCR- 2021/04/28
CRDT- 2021/05/02 20:52
PHST- 2020/12/21 00:00 [received]
PHST- 2021/03/30 00:00 [revised]
PHST- 2021/03/30 00:00 [accepted]
PHST- 2021/05/03 06:00 [pubmed]
PHST- 2021/07/06 06:00 [medline]
PHST- 2021/05/02 20:52 [entrez]
PHST- 2021/04/28 00:00 [pmc-release]
AID - S2213-2317(21)00113-0 [pii]
AID - 101965 [pii]
AID - 10.1016/j.redox.2021.101965 [doi]
PST - ppublish
SO  - Redox Biol. 2021 Jul;43:101965. doi: 10.1016/j.redox.2021.101965. Epub 2021 Apr 
      28.