Mitochondrial MUL1 E3 ubiquitin ligase regulates Hypoxia Inducible Factor (HIF-1α) and metabolic reprogramming by modulating the UBXN7 cofactor protein

• Published in: Scientific reports Vol. 10; no. 1; p. 1609
• Main Authors: Cilenti, Lucia, Di Gregorio, Jacopo, Ambivero, Camilla T., Andl, Thomas, Liao, Ronglih, Zervos, Antonis S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-01-2020; Nature Publishing Group
• Subjects: 13/95; 631/80/458/582; 692/4028/67/2327; 82/1; 82/29; 82/58; 82/80; 82/83; 96/106; 96/109; 96/31; 96/63; Adaptor Proteins, Signal Transducing - metabolism; Apoptosis; Cell Line; Cell Line, Tumor; Cytoplasm; Glycolysis; Glycolysis - physiology; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immune response; Inactivation; Innate immunity; Kinases; Metabolism; Mitochondria; Mitochondria - metabolism; Mitochondrial Dynamics - physiology; Mitochondrial Membranes - metabolism; multidisciplinary; Oxidative phosphorylation; Phosphorylation; Proteins; Science; Science (multidisciplinary); Topology; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Ubiquitination - physiology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-58484-8

MUL1 is a multifunctional E3 ubiquitin ligase anchored in the outer mitochondrial membrane with its RING finger domain facing the cytoplasm. MUL1 participates in various biological pathways involved in apoptosis, mitochondrial dynamics, and innate immune response. The unique topology of MUL1 enables it to “sense” mitochondrial stress in the intermembrane mitochondrial space and convey these signals through the ubiquitination of specific cytoplasmic substrates. We have identified UBXN7, the cofactor protein of the CRL2
VHL
ligase complex, as a specific substrate of MUL1 ligase. CRL2
VHL
ligase complex regulates HIF-1α protein levels under aerobic (normoxia) or anaerobic (hypoxia) conditions. Inactivation of MUL1 ligase leads to accumulation of UBXN7, with concomitant increase in HIF-1α protein levels, reduction in oxidative phosphorylation, and increased glycolysis. We describe a novel pathway that originates in the mitochondria and operates upstream of the CRL2
VHL
ligase complex. Furthermore, we delineate the mechanism by which the mitochondria, through MUL1 ligase, can inhibit the CRL2
VHL
complex leading to high HIF-1α protein levels and a metabolic shift to glycolysis under normoxic conditions.