Fig. 4: Loss of mitochondrial complex I in lung epithelial cells induces a robust ISR that precludes alveolar development.
From: Mitochondrial integrated stress response controls lung epithelial cell fate
a,b, RNA-seq analysis of lung epithelial cells isolated from 35-day-old mice (NDUFS2 control n = 8; NDUFS2 control/NDI1 n = 7; NDUFS2 cKO n = 7; NDUFS2 cKO/NDI1 n = 8 mice). a, Heat map of ATF transcripts and Ddit3. b, Heat map of ISR signature gene transcripts. c, UMAP plot showing expression of Atf genes in single-cell RNA-seq analysis of epithelial cells. d, UMAP displaying the level of ISR enrichment score calculated from the overall expression of ISR genes in each epithelial cell. Darker colour indicates a higher ISR enrichment score and thus a highly enriched ISR gene signature. e, Violin plots of ISR enrichment scores in epithelial subclusters. P < 2.2 × 10−16 by Kruskal–Wallis test. Transitional cells and Transitional-Lyz1+ cells have more enriched ISR gene signatures than other epithelial cells (***adjusted P < 1.0 × 10−29 by post hoc pairwise Mann–Whitney test with Holm method; P values are in the Source Data). f, The ISRIB reduces NDUFS2 cKO lethality. Survival of NDUFS2 cKO mice with or without ISRIB (NDUFS2 cKO n = 15; NDUFS2 cKO + ISRIB n = 27 mice; P < 0.0001 by log-rank test) and NDUFS2 control mice with ISRIB (NDUFS2 control + ISRIB n = 14 mice).
