Fig. 2: PAMT-001 inhibits mitochondrial respiration and distorts mitochondrial structure.
From: A novel PAAoptosis-inducing ERRα-targeting compound for combating hematopoietic and solid cancers
A Normalized enrichment score (NES) plot of the bottom 10 pathways via gene set enrichment analysis (GSEA) of PAMT-001-treated KG1α cells. B GSEA against Hallmark: oxidative phosphorylation. Genes were ranked based on fold changes between ERRα-high and -low (left), vehicle and XCT-790 (middle), and vehicle and PAMT-001 (right). Oxygen consumption rate (OCR) decreased with PAMT-001 treatment in KG1α (C) and HL-60 (D) cells. For each time point, mean ± SD value of OCR evaluated via Seahorse XF analysis is presented (n = 4 for KG1α; n = 5 for HL-60). Summary of OCR for mitochondrial respiration-related markers (basal and maximal respiration, proton leakage, and ATP production) of KG1α (E) and HL-60 (F) cells. P-values were calculated using one-way ANOVA (E) and two-tailed t-test (F). G Quantification of the expression of OXPHOS genes (NDUFS3, UQCRFS1, COX5A, and COX5B) using qRT-PCR in PAMT-001-treated KG1α cells (5 μM, 12 h). P-values were calculated using a two-tailed t-test (mean ± SD, n = 3). H Protein levels of OXHPOS complexes (NDUFA9, SDHA, UQCRC2, COX IV, and ATP5A) in response to PAMT-001 treatment (5 μM, 12 h) in KG1α cells. I GSEA against Reactome: cristae formation. Genes were ranked based on fold changes between ERRα-high and -low (left), vehicle and XCT-790 (middle), and vehicle and PAMT-001 (right). J Representative transmission electron microscopy images of vehicle-treated- or PAMT-001-treated HL-60 cells. Mitochondria of PAMT-001-treated cells showed mitochondrial damage, such as the disappearance and widening of cristae. Quantification of the mitochondrial width (K) and circularity (L) in 18 randomly selected mitochondria from five cells (J). P-values were calculated using a two-tailed t-test (mean ± SD, n = 18).
