{"doi":"10.1016/j.jbc.2023.104761","title":"An evolving view of complex II—noncanonical complexes, megacomplexes, respiration, signaling, and beyond","abstract":"Mitochondrial complex II is traditionally studied for its participation in two key respiratory processes: the electron transport chain and the Krebs cycle. There is now a rich body of literature explaining how complex II contributes to respiration. However, more recent research shows that not all of the pathologies associated with altered complex II activity clearly correlate with this respiratory role. Complex II activity has now been shown to be necessary for a range of biological processes peripherally related to respiration, including metabolic control, inflammation, and cell fate. Integration of findings from multiple types of studies suggests that complex II both participates in respiration and controls multiple succinate-dependent signal transduction pathways. Thus, the emerging view is that the true biological function of complex II is well beyond respiration. This review uses a semichronological approach to highlight major paradigm shifts that occurred over time. Special emphasis is given to the more recently identified functions of complex II and its subunits because these findings have infused new directions into an established field. Mitochondrial complex II is traditionally studied for its participation in two key respiratory processes: the electron transport chain and the Krebs cycle. There is now a rich body of literature explaining how complex II contributes to respiration. However, more recent research shows that not all of the pathologies associated with altered complex II activity clearly correlate with this respiratory role. Complex II activity has now been shown to be necessary for a range of biological processes peripherally related to respiration, including metabolic control, inflammation, and cell fate. Integration of findings from multiple types of studies suggests that complex II both participates in respiration and controls multiple succinate-dependent signal transduction pathways. Thus, the emerging view is that the true biological function of complex II is well beyond respiration. This review uses a semichronological approach to highlight major paradigm shifts that occurred over time. Special emphasis is given to the more recently identified functions of complex II and its subunits because these findings have infused new directions into an established field. Respiratory complex II (Fig. 1A, succinate dehydrogenase (SDH), canonically SDHA-SDHB-SDHC-SDHD, but with exceptions) is a heterotetrameric membrane-spanning enzyme first described in 1909 (1Thunberg T. Studien über die beeinflussung des gasaustausches des überlebenden froschmuskels durch verschiedene stoffe.Skand. Archiv. Pysiol. 1909; 22: 430-436Crossref Scopus (0) Google Scholar) and studied in its purified form for around a century. It has been long established that complex II is a key player in multiple respiratory processes (2Cecchini G. Function and structure of complex II of the respiratory chain.Annu. Rev. Biochem. 2003; 72: 77-109Crossref PubMed Scopus (365) Google Scholar, 3Cecchini G. Respiratory complex II: role in cellular physiology and disease.Biochim. Biophys. Acta. 2013; 1827: 541-542Crossref PubMed Scopus (19) Google Scholar). The first described role of complex II was as a bioenergetic complex catalyzing two distinct redox reactions in mitochondrial aerobic respiration (Fig. 1, B and C) (2Cecchini G. Function and structure of complex II of the respiratory chain.Annu. Rev. Biochem. 2003; 72: 77-109Crossref PubMed Scopus (365) Google Scholar, 3Cecchini G. Respiratory complex II: role in cellular physiology and disease.Biochim. Biophys. Acta. 2013; 1827: 541-542Crossref PubMed Scopus (19) Google Scholar, 4Iverson T.M. Catalytic mechanisms of complex II enzymes: a structural perspective.Biochim. Biophys. Acta. 2013; 1827: 648-657Crossref PubMed Scopus (48) Google Scholar). Here, complex II links oxidative phosphorylation (Fig. 1D) with the Krebs cycle (Fig. 2). Because of the energetics of aerobic respiration, complex II works i","journal":"Journal of Biological Chemistry","year":2023,"id":320763,"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":47,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1032012,"name":"Prashant K. Singh","orcid":"0000-0002-4515-7621","position":1,"is_corresponding":false},{"id":315279,"name":"Gary Cecchini","orcid":"0000-0002-0571-1747","position":2,"is_corresponding":false},{"id":315280,"name":"T.M. Iverson","orcid":"0000-0001-8816-6352","position":0,"is_corresponding":true}],"reference_count":245,"raw_metadata":null,"created_at":"2026-07-19T01:07:27.434133Z","pmid":"37119852","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":[]}