Mitochondrial UQCC3 controls angiogenesis during embryonic development and tumor growth

Abstract

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.