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 pneumonia1–6. 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 890-897 |
| Number of pages | 8 |
| Journal | Nature |
| Volume | 620 |
| Issue number | 7975 |
| DOIs | |
| State | Published - Aug 24 2023 |
Funding
We thank the following core facilities at Northwestern University: Pulmonary NextGen Sequencing Core, Transgenic and Targeted Mutagenesis Laboratory, the Robert H. Lurie Cancer Center (RHLCCC) Metabolomics Core, Mouse Histology and Phenotyping Laboratory, and Northwestern University Center for Advanced Microscopy, supported by NCI CCSG P30-CA060553 awarded to the RHLCC. We thank P. Gao for performing our metabolomics runs and H. Abdala-Valencia for technical assistance with RNA-seq. We thank the following members of the Northwestern University, Department of Medicine, Division of Pulmonary and Critical Care: S. Weinberg, R. Grant, N. Markov and A. Misharin for their helpful comments and A. Chaker for assistance with mouse colony management. Some elements in Fig. were generated with BioRender.com . This work was supported by the National Institutes for Health (NIH): R35CA197532 to N.S.C.; P01HL071643 and P01AG049665 to N.S.C. and G.R.S.B.; K08HL143138 to S.H.; R01HL134800 to C.J.G.; T32 HL076139 to C.R.R.; and K08HL146943 to P.A.R. S.H. was supported by the American Heart Association Career Development Award (19CDA34630070), the Parker B. Francis Fellowship and the Doris Duke Charitable Foundation/Walder Foundation and Feinberg School of Medicine COVID-19 Fund to Retain Clinician Scientists. G.R.S.B. was supported by the Veterans Administration grant CX001777. M.L. and Y.S. were supported by the National Research Foundation of Korea (2022R1A2C2093050), KREONET (Korea Research Environment Open NETwork), which is managed and operated by KISTI (Korea Institute of Science and Technology Information) and the Dongguk University Research Fund. R.P.C. and M.M.H. were supported by the Northwestern University Pulmonary and Critical Care Cugell fellowship.
ASJC Scopus subject areas
- General