The mitochondrial calcium uniporter of pulmonary type 2 cells determines severity of acute lung injury.
The mitochondrial calcium uniporter of pulmonary type 2 cells determines severity of acute lung injury.
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DOI：
10.1038/s41467-022-33543-y
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发表时间：
2022-10-03
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
由于吸入病原体引起的急性肺损伤（ALI）导致高死亡率。对潜在的机制了解不够。在这里，通过活小鼠肺的光学成像，我们表明，一个关键的机制是细胞溶质Ca2+缓冲的活力，线粒体Ca2+单向转运体（MCU）在肺的表面活性物质分泌，肺泡2型细胞（AT 2）。缓冲增加了野生型小鼠的线粒体Ca2+和诱导表面活性剂分泌，但在AT2特异性MCU敲除的小鼠中没有。在基因敲除小鼠中，由于鼻内LPS滴注引起的ALI引起严重的肺水肿和死亡，这通过在LPS滴注之前补充表面活性剂来减轻，表明表面活性剂对肺泡水肿的保护作用。在野生型小鼠中，鼻内LPS或铜绿假单胞菌降低AT2 MCU。MCU丢失导致缓冲失效。MCU表达的自发恢复或MCU补充降低了由此产生的死亡率。通过MCU补充增强AT2线粒体缓冲，从而增强内源性表面活性剂分泌，可能是治疗ALI的一种方法。吸入病原体引起的急性肺损伤可导致死亡，但其机制尚不清楚。在这里，作者在小鼠中表明，肺泡2型细胞（AT 2）的线粒体钙单向转运体（MCU）的丧失损害了线粒体Ca2+缓冲和表面活性剂分泌，并增加了对LPS滴注的响应，表明MCU作为ALI的潜在治疗靶点。
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 Ca2+ buffering by the mitochondrial Ca2+ uniporter (MCU) in the lung’s surfactant-secreting, alveolar type 2 cells (AT2). The buffering increased mitochondrial Ca2+ 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 Ca2+ buffering and surfactant secretion, and increased mortality, in response to LPS instillation, suggesting the MCU as a potential therapeutic target in ALI.
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影响因子：
12.4
作者：
Gherardi G;Nogara L;Ciciliot S;Fadini GP;Blaauw B;Braghetta P;Bonaldo P;De Stefani D;Rizzuto R;Mammucari C
通讯作者：
Mammucari C
DOI：
10.1073/pnas.1321114111
发表时间：
2014-04-29
影响因子：
11.1
作者：
Kim, Seong-Jun;Syed, Gulam H.;Siddiqui, Aleem
通讯作者：
Siddiqui, Aleem
内膜的四十千克蛋白是线粒体钙Uniporter。
影响因子：
64.8
作者：
De Stefani, Diego;Raffaello, Anna;Teardo, Enrico;Szabo, Ildiko;Rizzuto, Rosario
通讯作者：
Rizzuto, Rosario
影响因子：
20.1
作者：
Dai DF;Johnson SC;Villarin JJ;Chin MT;Nieves-Cintrón M;Chen T;Marcinek DJ;Dorn GW 2nd;Kang YJ;Prolla TA;Santana LF;Rabinovitch PS
通讯作者：
Rabinovitch PS
影响因子：
3.3
作者：
BHATTACHARYA, J;CRUZ, T;BRAY, BA
通讯作者：
BRAY, BA