Carbon monoxide-induced TFEB nuclear translocation enhances mitophagy/mitochondrial biogenesis in hepatocytes and ameliorates inflammatory liver injury

Carbon monoxide (CO) can confer protection against cellular stress, whereas the potential involvement of autophagy and lysosomal biogenesis remains incompletely understood. We demonstrate here that the activation of protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) with CO increas...

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Published in:Cell death & disease 2018-10, Vol.9 (11), p.1060-16, Article 1060
Main Authors: Kim, Hyo Jeong, Joe, Yeonsoo, Rah, So-Young, Kim, Seul-Ki, Park, Se-Ung, Park, Jeongmin, Kim, Jin, Ryu, Jinhyun, Cho, Gyeong Jae, Surh, Young-Joon, Ryter, Stefan W, Kim, Uh-Hyun, Chung, Hun Taeg
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus - drug effects
Animals
Antimetabolites - pharmacology
Autophagy
Autophagy - drug effects
Autophagy - genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
Biomarkers - metabolism
Biosynthesis
Calcineurin
Calcineurin - genetics
Calcineurin - metabolism
Calcium (intracellular)
Carbon monoxide
Carbon Monoxide - pharmacology
Cellular stress response
Chemical and Drug Induced Liver Injury - genetics
Chemical and Drug Induced Liver Injury - metabolism
Chemical and Drug Induced Liver Injury - pathology
Chemical and Drug Induced Liver Injury - prevention & control
Cytochrome c
D-Galactosamine
eIF-2 kinase
eIF-2 Kinase - genetics
eIF-2 Kinase - metabolism
Endoplasmic reticulum
Galactosamine - administration & dosage
Galactosamine - antagonists & inhibitors
Gene Expression Regulation
Hepatocytes
Hepatocytes - drug effects
Hepatocytes - metabolism
Hepatocytes - pathology
Homeostasis
Inflammation
Inhalation
Kinases
Lipopolysaccharides
Lipopolysaccharides - administration & dosage
Lipopolysaccharides - antagonists & inhibitors
Liver
Liver - drug effects
Liver - metabolism
Liver - pathology
Lysosomes - drug effects
Lysosomes - metabolism
Male
Mice
Mice, Inbred C57BL
Mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondrial DNA
Mitophagy
Mitophagy - drug effects
Mitophagy - genetics
Nuclear transport
Organelle Biogenesis
Parkin protein
Phagocytosis
Protein kinase R
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
Signal Transduction
siRNA
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Summary:Carbon monoxide (CO) can confer protection against cellular stress, whereas the potential involvement of autophagy and lysosomal biogenesis remains incompletely understood. We demonstrate here that the activation of protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) with CO increased the nuclear translocation of transcription factor EB (TFEB). PERK activation by CO increased intracellular Ca concentration and the phosphatase activity of calcineurin against TFEB. Moreover, we found that in the deficiency of TFEB, CO not only failed to recruit Parkin to the mitochondria but also failed to increase expression of lysosomal genes such as Lamp1, CathB, and TPP1. Therefore, we suggest that CO increases mitophagy through TFEB nuclear translocation by PERK-calcinuerin activation. In addition, the inhibition of TFEB with siRNA against TFEB abrogated the increase of mtDNA with CO, markers of mitochondrial biogenesis such as PGC1α, NRF1, and TFAM, and the mitochondrial proteins COX II, COX IV, and cytochrome c. To investigate the effects of CO on mitochondrial homeostasis in vivo, mice were treated with lipopolysaccharide (LPS)/D-galactosamine (D-GalN). CO inhalation reduced liver injury after challenge with LPS/GalN. Furthermore, CO inhalation increased TFEB activation, mitophagy and mitochondrial biogenesis in mice treated with LPS/GalN. Our findings describe novel mechanisms underlying CO-dependent cytoprotection in hepatocytes and liver tissue via activation of TFEB-dependent mitophagy and associated induction of both lysosomal and mitochondrial biogenesis.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-018-1112-x