Fig. 3: Deficient mitophagy and dysfunctional mitochondrial biogenesis in the mutant TALs in ADTKD. | Nature Communications

Fig. 3: Deficient mitophagy and dysfunctional mitochondrial biogenesis in the mutant TALs in ADTKD.

From: MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice

Fig. 3

a Heatmap of downregulated mitophagy-associated genes with Benjamini-Hochberg adjusted p ≤ 0.05. GAGE analysis. RNA was isolated from Umod +/+ and Umod DEL/+ TALs from 16-week-old mice. n = 5 mice/group. b Representative immunoblot analysis monitoring mitophagy pathways in Umod +/+ and Umod DEL/+ TALs at 12 weeks. n = 3–4 mice/genotype. c Representative immunoblot analysis monitoring FIS1 in Umod +/+ and Umod DEL/+ TALs at 12 weeks. n = 3–4 mice/genotype. d Representative immunoblot analysis monitoring mitochondrial biogenesis markers in Umod +/+ and Umod DEL/+ TALs at 12 weeks. n = 3–4 mice/genotype. e Relative mRNA levels of mtDNA genes, normalized to 18 s, from Umod +/+ (n = 5) and Umod DEL/+ (n = 6–7) kidneys at 16 weeks. Two-tailed t-test, Mean ± SD. p = 0.0067 (for mt-Co1), 0.0119 (mt-Rnr2), 0.0026 (mt-Nd4), 0.0219 (mt-Cytb). f Representative immunoblot analysis monitoring ETC protein expression in UMOD-positive and UMOD-negative tubular epithelium from Umod +/+ and Umod DEL/+ kidneys at 12 weeks. n = 3–4 mice/genotype. g Measurement of mitochondrial respiration using an OROBOROS Oxygraph system in permeabilized WT and Umod DEL/+ TALs at 16 weeks following sequential additions of G + M + P; ADP; succinate and FCCP. n = 4/genotype. Two-tailed t-test, Mean ± SD. p = 0.0005 (for ADP), 0.0008 (Succinate), 0.0023 (FCCP). h PET/CT images post-68Ga-Galuminox injection were acquired from Umod +/+ and Umod DEL/+ mice at 16 weeks. Uptake of radiotracers in the kidneys (red arrows) and retention in the bladders (yellow arrows) were shown. i SUV analysis of 68Ga-Galuminox uptake in kidneys of the indicated genotypes. n = 8 kidneys/group. Two-tailed t-test, Mean ± SD. ****p < 0.0001. j Post-PET imaging biodistribution data (%ID/g) of Umod +/+ and Umod DEL/+ kidneys at 16 weeks. n = 8 kidneys/group. Two-tailed t-test, Mean ± SD. ***p = 0.00011. k TEM ultrastructural analysis on the renal tubules from Umod +/+ and Umod DEL/+ mice at 16 weeks. Red arrows indicate aggregates of swollen mitochondria with disrupted cristae, and black arrow indicates “myelin body”. Scale bar, 400 nm. Source data are provided as a Source Data file.

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