The mitochondrial calcium uniporter of pulmonary type 2 cells determines severity of acute lung injury

• Published in: Nature communications 2022-10, Vol.13 (1), p.5837-15, Article 5837
• Main Authors: Islam, Mohammad Naimul, Gusarova, Galina A., Das, Shonit R., Li, Li, Monma, Eiji, Anjaneyulu, Murari, Mthunzi, Liberty, Quadri, Sadiqa K., Owusu-Ansah, Edward, Bhattacharya, Sunita, Bhattacharya, Jahar
• Format: Article
• Language: English
• Subjects: 14; 14/1; 14/34; 14/35; 14/69; 59; 631/443/1784; 692/699/1785/3193; Acute Lung Injury - chemically induced; Alveoli; Animals; Buffers; Calcium; Calcium (mitochondrial); Calcium - metabolism; Calcium buffering; Calcium Channels; Calcium ions; Edema; Humanities and Social Sciences; Inhalation; Injuries; Lipopolysaccharides; Lipopolysaccharides - toxicity; Lung - metabolism; Lungs; Mice; Mice, Knockout; Mitochondria; Mortality; Mouse devices; multidisciplinary; Pathogens; Pseudomonas aeruginosa; Replenishment; Respiration; Science; Science (multidisciplinary); Secretion; Spontaneous recovery; Surface-Active Agents; Surfactants; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33543-y

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. Acute lung injury caused by inhalation of pathogens leads to mortality, but the mechanisms are unclear. Here, the authors show in mice that that loss of the mitochondrial calcium uniporter (MCU) of alveolar type 2 cells (AT2) impaired mitochondrial Ca 2+ buffering and surfactant secretion, and increased mortality, in response to LPS instillation, suggesting the MCU as a potential therapeutic target in ALI.