PMID- 36346745
OWN - NLM
STAT- MEDLINE
DCOM- 20221110
LR  - 20221222
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 11
DP  - 2022 Nov 8
TI  - Connexin 43 hemichannels regulate mitochondrial ATP generation, mobilization, and 
      mitochondrial homeostasis against oxidative stress.
LID - 10.7554/eLife.82206 [doi]
LID - e82206
AB  - Oxidative stress is a major risk factor that causes osteocyte cell death and bone 
      loss. Prior studies primarily focus on the function of cell surface expressed 
      Cx43 channels. Here, we reported a new role of mitochondrial Cx43 (mtCx43) and 
      hemichannels (HCs) in modulating mitochondria homeostasis and function in bone 
      osteocytes under oxidative stress. In murine long bone osteocyte-Y4 cells, the 
      translocation of Cx43 to mitochondria was increased under H(2)O(2)-induced 
      oxidative stress. H(2)O(2) increased the mtCx43 level accompanied by elevated 
      mtCx43 HC activity, determined by dye uptake assay. Cx43 knockdown (KD) by the 
      CRISPR-Cas9 lentivirus system resulted in impairment of mitochondrial function, 
      primarily manifested as decreased ATP production. Cx43 KD had reduced 
      intracellular reactive oxidative species levels and mitochondrial membrane 
      potential. Additionally, live-cell imaging results demonstrated that the proton 
      flux was dependent on mtCx43 HCs because its activity was specifically inhibited 
      by an antibody targeting Cx43 C-terminus. The co-localization and interaction of 
      mtCx43 and ATP synthase subunit F (ATP5J2) were confirmed by Forster resonance 
      energy transfer and a protein pull-down assay. Together, our study suggests that 
      mtCx43 HCs regulate mitochondrial ATP generation by mediating K(+), H(+), and ATP 
      transfer across the mitochondrial inner membrane and the interaction with 
      mitochondrial ATP synthase, contributing to the maintenance of mitochondrial 
      redox levels in response to oxidative stress.
CI  - (c) 2022, Zhang et al.
FAU - Zhang, Jingruo
AU  - Zhang J
AUID- ORCID: 0000-0002-3786-9856
AD  - Department of Biochemistry and Structural Biology, University of Texas Health 
      Science Center, San Antonio, United States.
FAU - Riquelme, Manuel A
AU  - Riquelme MA
AUID- ORCID: 0000-0002-1915-0434
AD  - Department of Biochemistry and Structural Biology, University of Texas Health 
      Science Center, San Antonio, United States.
FAU - Hua, Rui
AU  - Hua R
AD  - Department of Biochemistry and Structural Biology, University of Texas Health 
      Science Center, San Antonio, United States.
FAU - Acosta, Francisca M
AU  - Acosta FM
AUID- ORCID: 0000-0002-0171-9901
AD  - Department of Biochemistry and Structural Biology, University of Texas Health 
      Science Center, San Antonio, United States.
FAU - Gu, Sumin
AU  - Gu S
AD  - Department of Biochemistry and Structural Biology, University of Texas Health 
      Science Center, San Antonio, United States.
FAU - Jiang, Jean X
AU  - Jiang JX
AUID- ORCID: 0000-0002-2185-5716
AD  - Department of Biochemistry and Structural Biology, University of Texas Health 
      Science Center, San Antonio, United States.
LA  - eng
GR  - R01 AR072020/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20221108
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (Connexin 43)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Connexin 43/genetics/metabolism
MH  - *Hydrogen Peroxide/metabolism
MH  - Mitochondria/metabolism
MH  - Oxidative Stress
MH  - Homeostasis
MH  - Adenosine Triphosphate/metabolism
PMC - PMC9642995
OTO - NOTNLM
OT  - ATP synthase
OT  - cell biology
OT  - connexin 43
OT  - mouse
OT  - osteocytes
OT  - oxidative stress
OT  - proton
COIS- JZ, MR, RH, FA, SG No competing interests declared, JJ Reviewing editor, eLife
EDAT- 2022/11/09 06:00
MHDA- 2022/11/11 06:00
PMCR- 2022/11/08
CRDT- 2022/11/08 12:53
PHST- 2022/07/27 00:00 [received]
PHST- 2022/10/25 00:00 [accepted]
PHST- 2022/11/08 12:53 [entrez]
PHST- 2022/11/09 06:00 [pubmed]
PHST- 2022/11/11 06:00 [medline]
PHST- 2022/11/08 00:00 [pmc-release]
AID - 82206 [pii]
AID - 10.7554/eLife.82206 [doi]
PST - epublish
SO  - Elife. 2022 Nov 8;11:e82206. doi: 10.7554/eLife.82206.