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Angiogensis during embryonic development and tumor growth requires the crucial involvement of mitochondria, which provide energy for cell proliferation, produce angiogenic signaling molecules, and exhibit a different functional profile in these cells. However, the detailed mechanisms underlying the regulatory role of mitochondria in angiogenesis remain elusive and warrant. Here, we reported that a small assembly factor of complex III, ubiquitin-cytochrome c reductase complex assembly factor 3 (UQCC3), is indispensable for angiogenesis during embryonic development and tumor growth. Homozygous deletion of UQCC3 caused early embryonic lethality and impaired vascular development. UQCC3 knockout in tumor cells impaired tumor angiogenesis and inhibits tumor growth. Mechanistically, UQCC3 expression was significantly upregulated in a hypoxic environment, which stabilised hypoxia inducible factor-1α (HIF-1α) and provoked a significantly higher expression of VEGF. UQCC3 knockout reduced the production of mitochondrial reactive oxygen species (ROS), stabilzed HIF-1α, and VEGF expression, but supplementation of ROS can restore HIF-1α and VEGF levels, and vice versa. Finally, based on the analysis of TCGA database, having high levels of UQCC3 is associated with unfavorable outcomes across various types of tumors, indicating a significant role for UQCC3 in tumor progression.

The ‘angiogenic switch’ is critical for tumor progression. However, the pathological details and molecular mechanisms remain incompletely characterized. In this study, we established mammal xenografts in zebrafish to visually investigate the first vessel growth (angiogenic switch) in real-time, by inoculating tumor cells into the perivitelline space of live optically transparent Transgenic (flk1:EGFP) zebrafish larvae. Using this model, we found that hypoxia and hypoxia-inducible factor (HIF) signaling were unnecessary for the angiogenic switch, whereas vascular endothelial growth factor A gene (Vegfa) played a crucial role. Mechanistically, transcriptome analysis showed that the angiogenic switch was characterized by inhibition of translation, but not hypoxia. Phosphorylation of eukaryotic translation initiation factor 2 alpha (Eif2α) and the expression of Vegfa were increased in the angiogenic switch microtumors, and 3D tumor spheroids, and puromycin-treated tumor cells. Vegfa overexpression promoted early onset of the angiogenic switch, whereas Vegfa knockout prevented the first tumor vessel from sprouting. Pretreatment of tumor cells with puromycin promoted the angiogenic switch in vivo similarly to Vegfa overexpression, whereas Vegfa knockdown suppressed the increase. This study provides direc and dynamic in vivo evidences that inhibition of translation, but not hypoxia or HIF signaling promotes the angiogenic switch in tumor by increasing Vegfa transcription.