Original ContributionRedox regulation of mitophagy in the lung during murine Staphylococcus aureus sepsis
Section snippets
Materials
Antibodies were purchased as follows: heme oxygenase 1 (HO-1; Assay Designs), Beclin-1 (Cell Signaling), Nrf2 (Santa Cruz), p62 (Abcam), LC3 (Sigma–Aldrich), SOD2 (Abcam), 8-hydroxy-2-deoxyguanosine (8-OHdG; Genetex). Primers used for quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) were all obtained from Life Technologies (Atg5, Atg12, Beclin-1, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), SOD2, HO-1). Bafilomycin A1 (BFA) was purchased from LC
Pulmonary inflammation and oxidative stress during sepsis
To assess the pulmonary inflammatory responses to S. aureus peritonitis, we measured lung mRNA levels for the early phase proinflammatory cytokines IL-1β and TNF-α at 0, 6, 24, and 48 h. The IL-1β and TNF-α mRNA levels increased sharply at 24 to 48 h after clot implantation (Figs. 1A and B). Cellular inflammation was also greatly increased as shown by significantly elevated bronchoalveolar lavage (BAL) white blood cell count and BAL protein at 24 h (Figs. 1C and D). To indirectly measure levels of
Discussion
Our data demonstrate for the first time that S. aureus sepsis induces mitophagy in the distal lung by a redox-sensitive pathway. Moreover, this redox pathway plays a key role in intracellular mitochondrial quality control, specifically in the turnover of damaged mitochondria as well as in mitochondrial biogenesis. In our mouse model, we found increased early phase inflammatory cytokine elaboration in the lung, i.e., IL-1β and TNF-α, as well as evidence of end organ inflammation and ALI
Acknowledgment
The authors thank the Duke Center for Hyperbaric Medicine and Environmental Physiology as well as the Eugene E. Stead Foundation for their generous scholarships and support.
References (63)
Oxidative stress and mitochondrial dysfunction in sepsis
Br. J. Anaesth.
(2011)- et al.
Reactive oxygen species and cellular oxygen sensing
Free Radic. Biol. Med.
(2007) - et al.
Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis
Free Radic. Biol. Med.
(2011) - et al.
The Nrf2–antioxidant response element signaling pathway and its activation by oxidative stress
J. Biol. Chem.
(2009) - et al.
Molecular mechanism activating Nrf2–Keap1 pathway in regulation of adaptive response to electrophiles
Free Radic. Biol. Med.
(2004) - et al.
Signaling pathways in mitochondrial dysfunction and aging
Mech. Ageing Dev.
(2010) - et al.
Sepsis induces extensive autophagic vacuolization in hepatocytes: a clinical and laboratory-based study
Lab. Invest.
(2009) - et al.
Apnea produces excitotoxic hippocampal synapses and neuronal apoptosis
Exp. Neurol.
(2012) Methods for monitoring autophagy using GFP–LC3 transgenic mice
Autophagy in Mammalian Systems, Part B
(2009)- et al.
Urinary 8-hydroxydeoxyguanosine and its analogs as DNA marker of oxidative stress: development of an ELISA and measurement in both bladder and prostate cancers
Clin. Chim. Acta
(2003)
Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics
Clin. Chim. Acta
Mitochondria and reactive oxygen species
Free Radic. Biol. Med.
Heme oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression
J. Biol. Chem.
Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1
Cell
p62 at the crossroads of autophagy, apoptosis, and cancer
Cell
Autophagy suppresses tumorigenesis through elimination of p62
Cell
p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy
J. Biol. Chem.
Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice
Cell
p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription
J. Biol. Chem.
Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice
Free Radic. Biol. Med.
Current epidemiology of septic shock: the CUB-Réa Network
Am. J. Respir. Crit. Care Med.
The pathophysiology and treatment of sepsis
N. Engl. J. Med.
The role of mitochondrial dysfunction in sepsis-induced multi-organ failure
Virulence
Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways
PLoS One
Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis
Am. J. Respir. Crit. Care Med.
Role of BNIP3 and NIX in cell death, autophagy, and mitophagy
Cell Death Differ.
Under the ROS: Thiol network is the principal suspect for autophagy commitment
Autophagy
Regulation of mitochondrial biogenesis
Essays Biochem.
Activation of mitochondrial biogenesis by heme oxygenase-1-mediated NF-E2–related factor-2 induction rescues mice from lethal Staphylococcus aureus sepsis
Am. J. Respir. Crit. Care Med.
Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes
Oncogene
Keap1 regulates both cytoplasmic–nuclear shuttling and degradation of Nrf2 in response to electrophiles
Genes Cells
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2021, Life SciencesCitation Excerpt :This is further accompanied by a failure to upregulate mitochondrial fusion through biogenesis via NRF1/PGC-1α/Tfam axis [195]. Nrf2 may also function in ROS scavenging protective role through regulation of lung mitophagy in sepsis, which allows activation of mitochondrial biogenesis through the HO-1 system [196]. The blocking of excessive endotoxin-induced mitochondrial fission with Specific –factor 1 (Mdivi-1), which promotes Ser-637 phosphorylation of Drp-1, exerted beneficial effects such as attenuation of infiltration of inflammatory cells, lung water, attenuation of alveolar edema and hemorrhage.