Mitochondrial UQCC3 Modulates Hypoxia Adaptation by Orchestrating OXPHOS and Glycolysis in Hepatocellular Carcinoma

Abstract

Highlights d UQCC3 is indispensable for bioenergetic reprogramming of HCC cells in hypoxia d UQCC3 is required for mitochondrial homeostasis and OXPHOS in hypoxia d Deficiency of UQCC3 impairs glycolysis and HIF-1a stabilization in hypoxia d UQCC3 and ROS generate positive feedback in hypoxia

Organization of the Respiratory Supercomplexes in Cells with Defective Complex III: Structural Features and Metabolic Consequences

“…Noticeably, cells bearing the p.278Y>C MTCYB mutation impairing CIII activity without affecting SCs organization failed to increase lactate release [121], in accord with the clinical phenotype of patients, presenting lactic acidosis in the patient bearing the 18-bp MTCYB deletion [120], but not in that with the p.278Y>C mutation [145]. The molecular mechanism underlining this metabolic switch is unknown, although the possible role for UQCC3 may be worth investigating [88]. Interestingly, previous studies described benefits in lifespan and energetic function of defective CI by interventions targeting NADH elevation, such as supplementation with NAD-precursor [146] inhibition of mTOR [147] and of mitochondrial serine catabolism [148], as well as hypoxia treatment [149].…”

“…The best-characterized is UQCC3 (ubiquinol-cytochrome c reductase complex assembly factor 3; also known as C11orf83), which is involved in the early phase of CIII assembly and in the stabilization of CIII-containing SCs [86,87]. Interestingly, UQCC3 was reported to be indispensable for simultaneously maintaining both OXPHOS and glycolysis during hepatocarcinoma cells hypoxia adaption, suggesting a role in energetic reprogramming [88].…”

A flow-cytometry-based protocol for detection of mitochondrial ROS production under hypoxia

“…Mitochondrial ROS increased rapidly under hypoxia, and the difference could be detected within 10 min ( Yang et al., 2020 ). However, if there is no difference between the two groups, the two groups should be compared with the negative control group that was not subjected with mitoSOX staining.…”

“…Here, we use HepG2 cells, but the protocol can be applied to other cell lines. For complete details on the use and execution of this protocol, please refer to Yang et al. (2020) .…”

“…For complete details on the use and execution of this protocol, please refer to Yang et al. (2020) .…”