The Mitochondrial Calcium Uniporter of Pulmonary Type 2 Cells Determines Severity of ARDS

Islam, Mohammad Naimul; Gusarova, Galina A.; Das, Shonit R.; Li, Li; Monma, Eiji; Anjaneyulu, Murari; Owusu-Ansah, Edward; Bhattacharya, Sunita; Bhattacharya, Jahar

Acute lung immunity to inhaled pathogens elicits defensive pneumonitis that may convert to the Acute Respiratory Distress Syndrome (ARDS), causing high mortality. Mechanisms underlying the conversion are not understood, but are of intense interest because of the ARDS-induced mortality in the ongoing Covid-19 pandemic. Here, by optical imaging of live lungs we show that key to the lethality is the functional status of mitochondrial Ca2+ buffering across the mitochondrial Ca2+ uniporter (MCU) in the lung’s alveolar type 2 cells (AT2), which protect alveolar stability. In mice subjected to ARDS by airway exposure to lipopolysaccharide (LPS), or to Pseudomonas aeruginosa, there was marked loss of MCU expression in AT2. The ability of mice to survive ARDS depended on the extent to which the MCU expression recovered, indicating that the viability of Ca2+ buffering by AT2 mitochondria critically determines ARDS severity. Mitochondrial transfer to enhance AT2 MCU expression might protect against ARDS.