PMID- 35933403
OWN - NLM
STAT- MEDLINE
DCOM- 20220809
LR  - 20230119
IS  - 2041-4889 (Electronic)
VI  - 13
IP  - 8
DP  - 2022 Aug 6
TI  - Oxidative stress-mediated mitochondrial fission promotes hepatic stellate cell 
      activation via stimulating oxidative phosphorylation.
PG  - 689
LID - 10.1038/s41419-022-05088-x [doi]
LID - 689
AB  - Previous studies have demonstrated dysregulated mitochondrial dynamics in 
      fibrotic livers and hepatocytes. Little is currently known about how 
      mitochondrial dynamics are involved, nor is it clear how mitochondrial dynamics 
      participate in hepatic stellate cell (HSC) activation. In the present study, we 
      investigated the role of mitochondrial dynamics in HSC activation and the 
      underlying mechanisms. We verified that mitochondrial fission was enhanced in 
      human and mouse fibrotic livers and active HSCs. Moreover, increased 
      mitochondrial fission driven by fis1 overexpression could promote HSC activation. 
      Inhibiting mitochondrial fission using mitochondrial fission inhibitor-1 
      (Mdivi-1) could inhibit activation and induce apoptosis of active HSCs, 
      indicating that increased mitochondrial fission is essential for HSC activation. 
      Mdivi-1 treatment also induced apoptosis in active HSCs in vivo and thus 
      ameliorated CCl(4)-induced liver fibrosis. We also found that oxidative 
      phosphorylation (OxPhos) was increased in active HSCs, and OxPhos inhibitors 
      inhibited activation and induced apoptosis in active HSCs. Moreover, increasing 
      mitochondrial fission upregulated OxPhos, while inhibiting mitochondrial fission 
      downregulated OxPhos, suggesting that mitochondrial fission stimulates OxPhos 
      during HSC activation. Next, we found that inhibition of oxidative stress using 
      mitoquinone mesylate (mitoQ) and Tempol inhibited mitochondrial fission and 
      OxPhos and induced apoptosis in active HSCs, suggesting that oxidative stress 
      contributes to excessive mitochondrial fission during HSC activation. In 
      conclusion, our study revealed that oxidative stress contributes to enhanced 
      mitochondrial fission, which triggers OxPhos during HSC activation. Importantly, 
      inhibiting mitochondrial fission has huge prospects for alleviating liver 
      fibrosis by eliminating active HSCs.
CI  - (c) 2022. The Author(s).
FAU - Zhou, Yanni
AU  - Zhou Y
AD  - Key Lab of Transplant Engineering and Immunology of the Ministry of Health, 
      Laboratory of Transplant Immunology, West China Hospital, Sichuan University, 
      Chengdu, Sichuan, 610041, P. R. China.
FAU - Long, Dan
AU  - Long D
AD  - Key Lab of Transplant Engineering and Immunology of the Ministry of Health, 
      Laboratory of Transplant Immunology, West China Hospital, Sichuan University, 
      Chengdu, Sichuan, 610041, P. R. China.
FAU - Zhao, Ying
AU  - Zhao Y
AUID- ORCID: 0000-0001-9985-2227
AD  - Regeneration Medicine Research Center, West China Hospital, Sichuan University, 
      Chengdu, Sichuan, 610041, P. R. China.
FAU - Li, Shengfu
AU  - Li S
AD  - Key Lab of Transplant Engineering and Immunology of the Ministry of Health, 
      Laboratory of Transplant Immunology, West China Hospital, Sichuan University, 
      Chengdu, Sichuan, 610041, P. R. China.
FAU - Liang, Yan
AU  - Liang Y
AUID- ORCID: 0000-0003-1437-1446
AD  - Research Core Facility of West China Hospital, Sichuan University, Chengdu, 
      Sichuan, 610041, P. R. China.
FAU - Wan, Lin
AU  - Wan L
AD  - Regeneration Medicine Research Center, West China Hospital, Sichuan University, 
      Chengdu, Sichuan, 610041, P. R. China.
FAU - Zhang, Jingyao
AU  - Zhang J
AD  - Regeneration Medicine Research Center, West China Hospital, Sichuan University, 
      Chengdu, Sichuan, 610041, P. R. China.
FAU - Xue, Fulai
AU  - Xue F
AD  - Regeneration Medicine Research Center, West China Hospital, Sichuan University, 
      Chengdu, Sichuan, 610041, P. R. China.
FAU - Feng, Li
AU  - Feng L
AUID- ORCID: 0000-0001-5039-1255
AD  - Regeneration Medicine Research Center, West China Hospital, Sichuan University, 
      Chengdu, Sichuan, 610041, P. R. China. feng31@Sohu.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220806
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
SB  - IM
MH  - Animals
MH  - *Hepatic Stellate Cells/pathology
MH  - Humans
MH  - Liver Cirrhosis/pathology
MH  - Mice
MH  - *Mitochondrial Dynamics
MH  - Oxidative Phosphorylation
MH  - Oxidative Stress
PMC - PMC9357036
COIS- The authors declare no competing interests.
EDAT- 2022/08/07 06:00
MHDA- 2022/08/10 06:00
PMCR- 2022/08/06
CRDT- 2022/08/06 23:19
PHST- 2022/02/11 00:00 [received]
PHST- 2022/07/07 00:00 [accepted]
PHST- 2022/07/06 00:00 [revised]
PHST- 2022/08/06 23:19 [entrez]
PHST- 2022/08/07 06:00 [pubmed]
PHST- 2022/08/10 06:00 [medline]
PHST- 2022/08/06 00:00 [pmc-release]
AID - 10.1038/s41419-022-05088-x [pii]
AID - 5088 [pii]
AID - 10.1038/s41419-022-05088-x [doi]
PST - epublish
SO  - Cell Death Dis. 2022 Aug 6;13(8):689. doi: 10.1038/s41419-022-05088-x.