PMID- 30153269
OWN - NLM
STAT- MEDLINE
DCOM- 20190208
LR  - 20231213
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 13
IP  - 8
DP  - 2018
TI  - Heme oxygenase metabolites improve astrocytic mitochondrial function via a 
      Ca2+-dependent HIF-1alpha/ERRalpha circuit.
PG  - e0202039
LID - 10.1371/journal.pone.0202039 [doi]
LID - e0202039
AB  - Heme oxygenase-1 (HO-1) exerts beneficial effects, including angiogenesis and 
      energy metabolism via the hypoxia-inducible factor-1alpha (HIF-1alpha) and 
      peroxisome-proliferator-activating receptor-gamma coactivator-1alpha 
      (PGC-1alpha)/estrogen-related receptor alpha (ERRalpha) pathways, respectively, in 
      astrocytes. However, evidence of cross-talk between both pathways in HO 
      metabolite-mediated mitochondrial biogenesis has not been well elucidated. Here, 
      we found that HIF-1alpha was upregulated in astrocytes after ischemic brain injury 
      following exposure to the carbon monoxide (CO)-releasing compound CORM-2. 
      Experiments with pharmacological inhibitors and target-specific siRNAs revealed 
      that HIF-1alpha levels were highly correlated with increased PGC-1alpha and ERRalpha levels, 
      which were linked to the HO metabolites CO- and bilirubin-induced activation of 
      apical L-type Ca2+ channel and sequential Ca2+-dependent signal transduction. 
      Moreover, HIF-1alpha was stabilized in a proline hydroxylase-dependent manner by 
      transient induction of intracellular hypoxia via the PGC-1alpha/ERRalpha-induced 
      increases in mitochondrial biogenesis and oxygen consumption. HIF-1alpha knockdown 
      blocked HO-1 system-mediated transcriptional expression of ERRalpha, but not of 
      PGC-1alpha, suggesting a possible involvement of HIF-1alpha in ERRalpha-mediated 
      mitochondrial biogenesis. These data suggest that the HO-1-derived metabolites, 
      CO and bilirubin, elevate astrocytic mitochondrial function via a HIF-1alpha/ERRalpha 
      circuit coupled with L-type Ca2+ channel activation and PGC-1alpha-mediated oxygen 
      consumption. This circuit may play an important role in repairing neurovascular 
      function after focal ischemic brain injury by stimulating mitochondrial 
      biogenesis.
FAU - Choi, Yoon Kyung
AU  - Choi YK
AUID- ORCID: 0000-0003-0242-9612
AD  - Department of Integrative Bioscience and Biotechnology, Konkuk University, Seoul, 
      Republic of Korea.
FAU - Park, Joon Ha
AU  - Park JH
AD  - Department of Neurobiology, School of Medicine, Kangwon National University, 
      Chuncheon, Kangwon-do, Republic of Korea.
FAU - Yun, Jung-A
AU  - Yun JA
AD  - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon 
      National University, Chuncheon, Kangwon-do, Republic of Korea.
FAU - Cha, Jong-Ho
AU  - Cha JH
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Kim, Yonghee
AU  - Kim Y
AD  - Department of Integrative Bioscience and Biotechnology, Konkuk University, Seoul, 
      Republic of Korea.
FAU - Won, Moo-Ho
AU  - Won MH
AD  - Department of Neurobiology, School of Medicine, Kangwon National University, 
      Chuncheon, Kangwon-do, Republic of Korea.
FAU - Kim, Kyu-Won
AU  - Kim KW
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Republic of Korea.
FAU - Ha, Kwon-Soo
AU  - Ha KS
AD  - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon 
      National University, Chuncheon, Kangwon-do, Republic of Korea.
FAU - Kwon, Young-Guen
AU  - Kwon YG
AD  - Department of Biochemistry, College of Life Science and Biotechnology, Yonsei 
      University, Seoul, Republic of Korea.
FAU - Kim, Young-Myeong
AU  - Kim YM
AD  - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon 
      National University, Chuncheon, Kangwon-do, Republic of Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180828
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Receptors, Estrogen)
RN  - EC 1.14.14.18 (Heme Oxygenase (Decyclizing))
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Animals
MH  - Astrocytes/*metabolism
MH  - Brain Ischemia/genetics/metabolism/pathology
MH  - Calcium/*metabolism
MH  - Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism
MH  - Gene Expression
MH  - Heme Oxygenase (Decyclizing)/genetics/*metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Immunohistochemistry
MH  - Mice
MH  - Mitochondria/*metabolism
MH  - Models, Biological
MH  - Oxygen Consumption
MH  - Receptors, Estrogen/*metabolism
MH  - ERRalpha Estrogen-Related Receptor
PMC - PMC6112640
COIS- The authors have declared that no competing interests exist.
EDAT- 2018/08/29 06:00
MHDA- 2019/02/09 06:00
PMCR- 2018/08/28
CRDT- 2018/08/29 06:00
PHST- 2018/02/07 00:00 [received]
PHST- 2018/07/26 00:00 [accepted]
PHST- 2018/08/29 06:00 [entrez]
PHST- 2018/08/29 06:00 [pubmed]
PHST- 2019/02/09 06:00 [medline]
PHST- 2018/08/28 00:00 [pmc-release]
AID - PONE-D-18-04240 [pii]
AID - 10.1371/journal.pone.0202039 [doi]
PST - epublish
SO  - PLoS One. 2018 Aug 28;13(8):e0202039. doi: 10.1371/journal.pone.0202039. 
      eCollection 2018.