Regulation of Metabolism by Mitochondrial MUL1 E3 Ubiquitin Ligase

• Published in: Frontiers in cell and developmental biology Vol. 10; p. 904728
• Main Authors: Cilenti, Lucia, Mahar, Rohit, Di Gregorio, Jacopo, Ambivero, Camilla T, Merritt, Matthew E, Zervos, Antonis S
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 29-06-2022
• Subjects: Akt2; Cell and Developmental Biology; HIF-1α; metabolic flux; mitochondrial metabolism; MUL1; MUL1; HIF-1α; metabolic flux; Akt2; mitochondrial metabolism
• ISSN: 2296-634X; 2296-634X
• DOI: 10.3389/fcell.2022.904728

MUL1 is a multifunctional E3 ubiquitin ligase that is involved in various pathophysiological processes including apoptosis, mitophagy, mitochondrial dynamics, and innate immune response. We uncovered a new function for MUL1 in the regulation of mitochondrial metabolism. We characterized the metabolic phenotype of MUL1(-/-) cells using metabolomic, lipidomic, gene expression profiling, metabolic flux, and mitochondrial respiration analyses. In addition, the mechanism by which MUL1 regulates metabolism was investigated, and the transcription factor HIF-1α, as well as the serine/threonine kinase Akt2, were identified as the mediators of the MUL1 function. MUL1 ligase, through K48-specific polyubiquitination, regulates both Akt2 and HIF-1α protein level, and the absence of MUL1 leads to the accumulation and activation of both substrates. We used specific chemical inhibitors and activators of HIF-1α and Akt2 proteins, as well as Akt2(-/-) cells, to investigate the individual contribution of HIF-1α and Akt2 proteins to the MUL1-specific phenotype. This study describes a new function of MUL1 in the regulation of mitochondrial metabolism and reveals how its downregulation/inactivation can affect mitochondrial respiration and cause a shift to a new metabolic and lipidomic state.