PMID- 33719895
OWN - NLM
STAT- MEDLINE
DCOM- 20220321
LR  - 20230921
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 17
IP  - 11
DP  - 2021 Nov
TI  - AMPK protects against alcohol-induced liver injury through UQCRC2 to up-regulate 
      mitophagy.
PG  - 3622-3643
LID - 10.1080/15548627.2021.1886829 [doi]
AB  - Recent reports indicated that mitophagy protects against alcohol-induced liver 
      injury, which helps remove damaged mitochondria to reduce the accumulation of 
      reactive oxygen species (ROS). AMP-activated protein kinase (AMPK) has been 
      recently used in ALD (alcoholic liver disease) and mitochondrial dysfunction 
      research. However, the inner mechanism, whether AMPK can regulate mitophagy in 
      ALD, remains unknown. Here we found that AMPK can significantly reduce 
      alcohol-induced liver injury and enhances hepatocytes' mitophagy level. Next, we 
      identified that AMPK rescued alcohol-induced low expression of UQCRC2 
      (ubiquinol-cytochrome c reductase core protein 2). Interestingly, UQCRC2 
      knockdown (KD) treatment causes impaired mitophagy, whereas UQCRC2 overexpression 
      (OE) can significantly increase mitophagy to attenuate liver injury. Also, we 
      identified that AMPK indirectly upregulates UQCRC2 protein level, and RNA-seq, 
      chromatin immunoprecipitation (ChIP) assay, bioinformatics, and luciferase assays 
      helped us understand that AMPK enhanced UQCRC2 gene transcription through 
      activating NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2). Our results 
      demonstrate that AMPK regulating UQCRC2 is a significant mitochondrial event in 
      mitophagy. It identifies a new signaling axis, AMPK-NFE2L2-UQCRC2, in the 
      regulation of mitophagy levels in the liver, suggesting a possible therapeutic 
      strategy to treat ALD.Abbreviations: AAV: AENO-associated virus; ALD: alcoholic 
      liver disease; AMPK: AMP-activated protein kinase; BUN: blood urea nitrogen; H&E: 
      hematoxylin and eosin; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ChIP: 
      chromatin immunoprecipitation assay; CO-IP: co-immunoprecipitation; COPD: chronic 
      obstructive pulmonary disease; EM: electron microscope; GOT1/AST: 
      glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvic transaminase; IF: 
      immunofluorescence; IHC: immunohistochemistry; KD: knockdown; MAP1LC3/LC3: 
      microtubule associated protein 1 light chain protein 3; MTDR: MitoTracker Deep 
      Red; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; mtDNA: mitochondrial DNA; 
      MTRC: MitoTracker Red CMXRos; OCR: Oxygen consumption rate; OE: overexpress; 
      PINK1: PTEN induced kinase 1; qRT-PCR: quantitative real-time PCR; ROS: reactive 
      oxygen species; SD: standard deviation; SOD2: superoxide dismutase 2; UQCRC2: 
      ubiquinol-cytochrome c reductase core protein 2; WB: western blot; DeltaPsi: 
      mitochondrial membrane potential.
FAU - Lu, Xinyi
AU  - Lu X
AUID- ORCID: 0000-0002-9634-2333
AD  - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of 
      Pharmacy, Anhui Medical University, Hefei, Anhui, China.
FAU - Xuan, Wenting
AU  - Xuan W
AD  - Department of Anesthesiology, Drum Tower Hospital, Medical College of Nanjing 
      University, Nanjing, China.
FAU - Li, Juanjuan
AU  - Li J
AD  - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of 
      Pharmacy, Anhui Medical University, Hefei, Anhui, China.
FAU - Yao, Hongwei
AU  - Yao H
AD  - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of 
      Pharmacy, Anhui Medical University, Hefei, Anhui, China.
FAU - Huang, Cheng
AU  - Huang C
AD  - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of 
      Pharmacy, Anhui Medical University, Hefei, Anhui, China.
FAU - Li, Jun
AU  - Li J
AD  - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of 
      Pharmacy, Anhui Medical University, Hefei, Anhui, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210314
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (Carrier Proteins)
RN  - 0 (UQCRC2 protein, mouse)
RN  - 0 (ubiquinone-binding proteins)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 7.1.1.8 (Electron Transport Complex III)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Animals
MH  - Carrier Proteins/metabolism
MH  - Disease Models, Animal
MH  - Electron Transport Complex III/*metabolism
MH  - Humans
MH  - Liver/metabolism/pathology
MH  - Liver Diseases, Alcoholic/*metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Mitophagy
MH  - Up-Regulation
PMC - PMC8632272
OTO - NOTNLM
OT  - AMPK
OT  - bioinformatics
OT  - mitophagy
OT  - rna-seq
OT  - transcription factor
OT  - uqcrc2
COIS- The authors declare no conflict of interest.
EDAT- 2021/03/16 06:00
MHDA- 2022/03/22 06:00
PMCR- 2021/03/14
CRDT- 2021/03/15 12:46
PHST- 2021/03/16 06:00 [pubmed]
PHST- 2022/03/22 06:00 [medline]
PHST- 2021/03/15 12:46 [entrez]
PHST- 2021/03/14 00:00 [pmc-release]
AID - 1886829 [pii]
AID - 10.1080/15548627.2021.1886829 [doi]
PST - ppublish
SO  - Autophagy. 2021 Nov;17(11):3622-3643. doi: 10.1080/15548627.2021.1886829. Epub 
      2021 Mar 14.