美国西北大学Navdeep S. Chandel等研究人员合作发现，线粒体综合应激反应控制肺上皮细胞的命运。相关论文于2023年8月9日在线发表在《自然》杂志上。
研究人员表示，肺泡上皮1型（AT1）细胞是在血液和空气之间传递氧气和二氧化碳的必要细胞。肺泡上皮2型（AT2）细胞是部分确定的干细胞群，在出生后的肺泡发育过程中产生AT1细胞，并在甲型流感和SARS-CoV-2肺炎后进行修复。人们对肺上皮细胞命运的代谢调控知之甚少。
研究人员报告了小鼠妊娠期肺上皮细胞中线粒体电子传递链复合物I亚基Ndufs2的缺失会导致小鼠在出生后肺泡发育过程中死亡。受影响的小鼠显示出具有AT2和AT1细胞特征的肥大细胞，即过渡细胞。哺乳动物线粒体复合物I由45个亚基组成，可再生NAD+并泵送质子。酵母NADH脱氢酶（NDI1）蛋白可再生NAD+，但无质子泵作用，这种条件表达足以纠正肺泡发育异常并避免致死。单细胞RNA测序显示，过渡细胞中富含综合应激反应（ISR）基因。施用ISR抑制剂或NAD+前体可减少上皮细胞中的ISR基因特征，并在线粒体复合体I功能缺失的情况下部分挽救致死率。
值得注意的是，肺上皮细胞特异性线粒体电子传递链复合物II亚基Sdhd的缺失（该亚基可维持NAD+的再生）不会引发ISR的高度激活或致死。这些发现突显了线粒体复合物I依赖于NAD+的再生在新生儿肺泡发育过程中通过防止病理性ISR诱导来指导细胞命运的意外需求。
附：英文原文
Title: Mitochondrial integrated stress response controls lung epithelial cell fate
Author: Han, SeungHye, Lee, Minho, Shin, Youngjin, Giovanni, Regina, Chakrabarty, Ram P., Herrerias, Mariana M., Dada, Laura A., Flozak, Annette S., Reyfman, Paul A., Khuder, Basil, Reczek, Colleen R., Gao, Lin, Lopz-Barneo, Jos, Gottardi, Cara J., Budinger, G. R. Scott, Chandel, Navdeep S.
Issue&Volume: 2023-08-09
Abstract: Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood and air. Alveolar epithelial type 2 (AT2) cells serve as a partially committed stem cell population, producing AT1 cells during postnatal alveolar development and repair after influenza A and SARS-CoV-2 pneumonia1,2,3,4,5,6. Little is known about the metabolic regulation of the fate of lung epithelial cells. Here we report that deleting the mitochondrial electron transport chain complex I subunit Ndufs2 in lung epithelial cells during mouse gestation led to death during postnatal alveolar development. Affected mice displayed hypertrophic cells with AT2 and AT1 cell features, known as transitional cells. Mammalian mitochondrial complex I, comprising 45 subunits, regenerates NAD+ and pumps protons. Conditional expression of yeast NADH dehydrogenase (NDI1) protein that regenerates NAD+ without proton pumping7,8 was sufficient to correct abnormal alveolar development and avert lethality. Single-cell RNA sequencing revealed enrichment of integrated stress response (ISR) genes in transitional cells. Administering an ISR inhibitor9,10 or NAD+ precursor reduced ISR gene signatures in epithelial cells and partially rescued lethality in the absence of mitochondrial complex I function. Notably, lung epithelial-specific loss of mitochondrial electron transport chain complex II subunit Sdhd, which maintains NAD+ regeneration, did not trigger high ISR activation or lethality. These findings highlight an unanticipated requirement for mitochondrial complex I-dependent NAD+ regeneration in directing cell fate during postnatal alveolar development by preventing pathological ISR induction.
DOI: 10.1038/s41586-023-06423-8
Source: https://www.nature.com/articles/s41586-023-06423-8
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
