The mitochondrial calcium uniporter of pulmonary type 2 cells determines severity of acute lung injury.
Mohammad Naimul IslamGalina A GusarovaShonit R DasLi LiEiji MonmaMurari AnjaneyuluLiberty MthunziSadiqa K QuadriEdward Owusu-AnsahSunita BhattacharyaJahar BhattacharyaPublished in: Nature communications (2022)
Acute Lung Injury (ALI) due to inhaled pathogens causes high mortality. Underlying mechanisms are inadequately understood. Here, by optical imaging of live mouse lungs we show that a key mechanism is the viability of cytosolic Ca 2+ buffering by the mitochondrial Ca 2+ uniporter (MCU) in the lung's surfactant-secreting, alveolar type 2 cells (AT2). The buffering increased mitochondrial Ca 2+ and induced surfactant secretion in wild-type mice, but not in mice with AT2-specific MCU knockout. In the knockout mice, ALI due to intranasal LPS instillation caused severe pulmonary edema and mortality, which were mitigated by surfactant replenishment prior to LPS instillation, indicating surfactant's protective effect against alveolar edema. In wild-type mice, intranasal LPS, or Pseudomonas aeruginosa decreased AT2 MCU. Loss of MCU abrogated buffering. The resulting mortality was reduced by spontaneous recovery of MCU expression, or by MCU replenishment. Enhancement of AT2 mitochondrial buffering, hence endogenous surfactant secretion, through MCU replenishment might be a therapy against ALI.
Keyphrases
- wild type
- oxidative stress
- induced apoptosis
- inflammatory response
- pseudomonas aeruginosa
- lipopolysaccharide induced
- cardiovascular events
- cell cycle arrest
- pulmonary hypertension
- lps induced
- cystic fibrosis
- anti inflammatory
- high resolution
- risk factors
- cell death
- metabolic syndrome
- early onset
- endoplasmic reticulum stress
- adipose tissue
- endothelial cells
- drug resistant
- multidrug resistant
- photodynamic therapy
- cell therapy