{"doi":"10.3389/fendo.2021.710698","title":"Knock-Out of DHTKD1 Alters Mitochondrial Respiration and Function, and May Represent a Novel Pathway in Cardiometabolic Disease Risk","abstract":"Cardiometabolic disease affects the majority of individuals worldwide. The metabolite α-aminoadipic acid (2-AAA) was identified as a biomarker of Type 2 Diabetes (T2D). However, the mechanisms underlying this association remain unknown. DHTKD1 , a central gene in the 2-AAA pathway, has been linked to 2-AAA levels and metabolic phenotypes. However, relatively little is known about its function. Here we report that DHTKD1 knock-out (KO) in HAP-1 cells leads to impaired mitochondrial structure and function. Despite impaired mitochondrial respiration and less ATP production, normal cell proliferation rate is maintained, potentially through a series of compensatory mechanisms, including increased mitochondrial content and Akt activation, p38, and ERK signaling. Common variants in DHTKD1 associate with Type 2 Diabetes and cardiometabolic traits in large genome-wide associations studies. These findings highlight the vital role of DHTKD1 in cellular metabolism and establish DHTKD1-mediated mitochondrial dysfunction as a potential novel pathway in cardiometabolic disease.","journal":"Frontiers in Endocrinology","year":2021,"id":172766,"datarank":0.9240442060459129,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.43532972534269054,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.43532972534269054,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":20,"citers_with_citation_signal":17,"citers_with_endowment":17,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":416181,"name":"M. Wade Calcutt","orcid":"0000-0002-8002-4699","position":1,"is_corresponding":false},{"id":98916,"name":"Jane F. Ferguson","orcid":"0000-0001-6896-1025","position":2,"is_corresponding":false},{"id":709187,"name":"Chuan Wang","orcid":"0000-0001-5165-8273","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:46:41.424716Z","pmid":"34484123","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":[]}