{"doi":"10.3389/fcell.2022.904728","title":"Regulation of Metabolism by Mitochondrial MUL1 E3 Ubiquitin Ligase","abstract":"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.","journal":"Frontiers in Cell and Developmental Biology","year":2022,"id":259952,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":317135,"name":"Rohit Mahar","orcid":"0000-0002-9801-4173","position":1,"is_corresponding":false},{"id":336853,"name":"Jacopo Di Gregorio","orcid":"0000-0001-8865-2967","position":2,"is_corresponding":false},{"id":336854,"name":"Camilla T. Ambivero","orcid":"0000-0002-8717-2993","position":3,"is_corresponding":false},{"id":317136,"name":"Matthew E. Merritt","orcid":"0000-0003-4617-9651","position":4,"is_corresponding":false},{"id":338324,"name":"Antonis S. Zervos","orcid":null,"position":5,"is_corresponding":false},{"id":338323,"name":"Lucia Cilenti","orcid":null,"position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T00:26:03.189798Z","pmid":"35846359","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}