TY - JOUR
T1 - Mitochondrial quality control in alveolar epithelial cells damaged by s. Aureus pneumonia in mice
AU - Suliman, Hagir B.
AU - Kraft, Bryan
AU - Bartz, Raquel
AU - Chen, Lingye
AU - Welty-Wolf, Karen E.
AU - Piantadosi, Claude A.
N1 - Funding Information:
This study was funded by National Institute of Allergy and Infectious Diseases Grant R01-AI-095424 (to C. A. Piantadosi, Principal Investigator).
Publisher Copyright:
© 2017 the American Physiological Society.
PY - 2017/10
Y1 - 2017/10
N2 - Mitochondrial damage is often overlooked in acute lung injury (ALI), yet most of the lung’s physiological processes, such as airway tone, mucociliary clearance, ventilation-perfusion (Va/Q) matching, and immune surveillance require aerobic energy provision. Because the cell’s mitochondrial quality control (QC) process regulates the elimination and replacement of damaged mitochondria to maintain cell survival, we serially evaluated mitochondrial biogenesis and mitophagy in the alveolar regions of mice in a validated Staphylococcus aureus pneumonia model. We report that apart from cell lysis by direct contact with microbes, modest epithelial cell death was detected despite significant mitochondrial damage. Cell death by TdT-mediated dUTP nick-end labeling staining occurred on days 1 and 2 postinoculation: apoptosis shown by caspase-3 cleavage was present on days 1 and 2, while necroptosis shown by increased levels of phospho- mixed lineage kinase domain-like protein (MLKL) and receptor-interacting serine/ threonine-protein kinase 1 (RIPK1) was present on day 1. Cell death in alveolar type I (AT1) cells assessed by bronchoalveolar lavage fluid receptor for advanced glycation end points (RAGE) levels was high, yet AT2 cell death was limited while both mitochondrial biogenesis and mitophagy were induced. These mitochondrial QC mechanisms were evaluated mainly in AT2 cells by localizing increases in citrate synthase content, increases in nuclear mitochondrial biogenesis regulators nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and increases in light chain 3B protein (LC3-I)/LC3II ratios. Concomitant changes in p62, Pink 1, and Parkin protein levels indicated activation of mitophagy. By confocal microscopy, mitochondrial biogenesis and mitophagy were often observed on day 1 within the same AT2 cells. These findings imply that mitochondrial QC activation in pneumoniadamaged AT2 cells promotes cell survival in support of alveolar function.
AB - Mitochondrial damage is often overlooked in acute lung injury (ALI), yet most of the lung’s physiological processes, such as airway tone, mucociliary clearance, ventilation-perfusion (Va/Q) matching, and immune surveillance require aerobic energy provision. Because the cell’s mitochondrial quality control (QC) process regulates the elimination and replacement of damaged mitochondria to maintain cell survival, we serially evaluated mitochondrial biogenesis and mitophagy in the alveolar regions of mice in a validated Staphylococcus aureus pneumonia model. We report that apart from cell lysis by direct contact with microbes, modest epithelial cell death was detected despite significant mitochondrial damage. Cell death by TdT-mediated dUTP nick-end labeling staining occurred on days 1 and 2 postinoculation: apoptosis shown by caspase-3 cleavage was present on days 1 and 2, while necroptosis shown by increased levels of phospho- mixed lineage kinase domain-like protein (MLKL) and receptor-interacting serine/ threonine-protein kinase 1 (RIPK1) was present on day 1. Cell death in alveolar type I (AT1) cells assessed by bronchoalveolar lavage fluid receptor for advanced glycation end points (RAGE) levels was high, yet AT2 cell death was limited while both mitochondrial biogenesis and mitophagy were induced. These mitochondrial QC mechanisms were evaluated mainly in AT2 cells by localizing increases in citrate synthase content, increases in nuclear mitochondrial biogenesis regulators nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and increases in light chain 3B protein (LC3-I)/LC3II ratios. Concomitant changes in p62, Pink 1, and Parkin protein levels indicated activation of mitophagy. By confocal microscopy, mitochondrial biogenesis and mitophagy were often observed on day 1 within the same AT2 cells. These findings imply that mitochondrial QC activation in pneumoniadamaged AT2 cells promotes cell survival in support of alveolar function.
KW - Acute lung injury
KW - Alveolar epithelial cells
KW - Mitochondria
KW - Mitophogy
KW - Quality control
UR - http://www.scopus.com/inward/record.url?scp=85030644555&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00197.2017
DO - 10.1152/ajplung.00197.2017
M3 - Article
C2 - 28663335
AN - SCOPUS:85030644555
SN - 1040-0605
VL - 313
SP - L699-L709
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 4
ER -