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

Abstract

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 Ca2+ 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.

Mechanisms and Functions of Mitophagy and Potential Roles in Renal Disease

“…Interestingly, the activities of both Nrf2 and TFEB were shown to be downregulated in DKD (Xiao et al, 2017;Zhao et al, 2018). With increasing evidence supporting the role of TFEB during mitophagy (Kim et al, 2018;Tan et al, 2019), the involvement of crosstalk between TFEB and Nrf2 in this process should be further investigated.…”

Effects of 5-aminolevulinic acid and sodium ferrous citrate on fibroblasts from individuals with mitochondrial diseases

“…HO-1, HO-1-derived bilirubin, biliverdin, and CO have been shown to have antioxidative and anti-inflammatory properties 11,20 . Furthermore, HO-1 and CO, which can be increased by ALA/SFC, have been shown to increase mtDNA copy number by enhanced protein expression of nuclear respiratory factor-1 (NRF1), peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α), and mitochondrial transcriptional factor A (TFAM) 8,14,21,22 . In this study, we observed that ALA/SFC upregulated mtDNA copy number, as well as HO-1 mRNA and protein in normal and patient-derived fibroblasts.…”

Targeting the Heme Oxygenase 1/Carbon Monoxide Pathway to Resolve Lung Hyper-Inflammation and Restore a Regulated Immune Response in Cystic Fibrosis

“…CO reduces the number of neutrophils in septic lungs by controlling transendothelial migration ( Mizuguchi et al., 2009 ). Moreover, at low concentrations, CO attenuates the lung inflammatory response in mice challenged with LPS or live bacteria ( Macgarvey et al., 2012 ; Wegiel et al., 2014b ; Wilson et al., 2017 ; Kim et al., 2018 ). It differentially and selectively inhibits LPS-induced expression of pro-inflammatory cytokines (e.g., TNF-α, IL-6), while increasing levels of anti-inflammatory molecules (e.g., IL-10, IL-1 receptor antagonist (IL-1Ra, PPAR - γ) ( Bilban et al., 2006 ; Haschemi et al., 2011 ; Piantadosi et al., 2011 ; Macgarvey et al., 2012 ; Uddin et al., 2015 ).…”

“…This may be a key mechanism in CO’s modulation of the MΦ response to infections. CO also induces mitochondrial and lysosomal biogenesis by activating the guanylate cyclase and the PI3K/AKT pathway, and upregulating transcription factors such as Nrf1, Transcription Factor A, mitochondrial (TFAM), Nrf2, Transcription Factor EB (TFEB), and PGC-1α ( Zuckerbraun et al., 2007 ; Piantadosi et al., 2011 ; Queiroga et al., 2012 ; Wegiel et al., 2013 ; Motterlini and Foresti, 2017 ; Kim et al., 2018 ). These data suggest that cellular CO primes MΦs to better respond to cellular stressors.…”