{"doi":"10.1101/2023.02.01.525989","title":"Elamipretide Improves ADP Sensitivity in Aged Mitochondria by Increasing Uptake through the Adenine Nucleotide Translocator (ANT)","abstract":"<jats:title>SUMMARY</jats:title>\n                <jats:p>\n                  Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment,\n                  <jats:italic>in vivo</jats:italic>\n                  heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>Abstract Figure</jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:label>Graphical Abstract.</jats:label>\n                    <jats:caption>\n                      <jats:title>ELAM Binds Directly to ANT and ATP Synthase and ELAM Treatment Improves ADP Sensitivity, Increases ATP Production, and Improves Physiological Function in Old Muscles.</jats:title>\n                      <jats:p>\n                        ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (Adenine nucleotide translocator), H\n                        <jats:sup>+</jats:sup>\n                        (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH\n                        <jats:sub>2</jats:sub>\n                        (flavin adenine dinucleotide), O\n                        <jats:sub>2</jats:sub>\n                        (oxygen), ELAM (elamipretide), −SH (free thiol), −SSG (glutathionylated protein).\n                      </jats:p>\n                    </jats:caption>\n                    <jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"525989v1_ufig1\" position=\"float\" orientation=\"portrait\"/>\n                  </jats:fig>\n                </jats:sec>","journal":null,"year":null,"id":661683,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":741118,"name":"Varun Kamat","orcid":"0009-0002-2635-8310","position":1,"is_corresponding":false},{"id":1727395,"name":"Sricharan Kannan","orcid":null,"position":2,"is_corresponding":false},{"id":1727396,"name":"Rudolph S. Stuppard","orcid":null,"position":3,"is_corresponding":false},{"id":320214,"name":"Jeremy Whitson","orcid":"0000-0002-5775-1142","position":4,"is_corresponding":false},{"id":1727397,"name":"Miguel Martin-Perez","orcid":null,"position":5,"is_corresponding":false},{"id":114348,"name":"Wei-Jun Qian","orcid":null,"position":6,"is_corresponding":false},{"id":79569,"name":"Michael J. MacCoss","orcid":"0000-0003-1853-0256","position":7,"is_corresponding":false},{"id":1727398,"name":"Judit Villen","orcid":null,"position":8,"is_corresponding":false},{"id":1727399,"name":"Peter Rabinovitch","orcid":null,"position":9,"is_corresponding":false},{"id":519718,"name":"Matthew D. Campbell","orcid":"0000-0002-6632-2606","position":10,"is_corresponding":false},{"id":273754,"name":"Ian R. Sweet","orcid":"0000-0002-7565-1663","position":11,"is_corresponding":false},{"id":252344,"name":"David J. Marcinek","orcid":"0000-0001-5187-2149","position":12,"is_corresponding":false},{"id":326505,"name":"Gavin Pharaoh","orcid":"0000-0001-7221-7346","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Elamipretide Improves ADP Sensitivity in Aged Mitochondria by Increasing Uptake through the Adenine Nucleotide Translocator (ANT)","abstract":"<jats:title>SUMMARY</jats:title>\n                <jats:p>\n                  Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment,\n                  <jats:italic>in vivo</jats:italic>\n                  heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>Abstract Figure</jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:label>Graphical Abstract.</jats:label>\n                    <jats:caption>\n                      <jats:title>ELAM Binds Directly to ANT and ATP Synthase and ELAM Treatment Improves ADP Sensitivity, Increases ATP Production, and Improves Physiological Function in Old Muscles.</jats:title>\n                      <jats:p>\n                        ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (Adenine nucleotide translocator), H\n                        <jats:sup>+</jats:sup>\n                        (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH\n                        <jats:sub>2</jats:sub>\n                        (flavin adenine dinucleotide), O\n                        <jats:sub>2</jats:sub>\n                        (oxygen), ELAM (elamipretide), −SH (free thiol), −SSG (glutathionylated protein).\n                      </jats:p>\n                    </jats:caption>\n                    <jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"525989v1_ufig1\" position=\"float\" orientation=\"portrait\"/>\n                  </jats:fig>\n                </jats:sec>","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36778398","pmcid":null,"openalex_id":"https://openalex.org/W4319232444","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"5T32AG066574-03","title":"Biological Mechanisms of Healthy Aging Training Grant"},{"funder_name":"National Institutes of Health","grant_id":"1P30AR074990-01","title":"UW Center for Translational Muscle Research (Overall Application)"},{"funder_name":"National Institutes of Health","grant_id":"5P01AG001751-20","title":"CORE--FLOW AND IMAGE CYTOMETRY"},{"funder_name":"National Institutes of Health","grant_id":"1R56AG070096-01A1","title":"Structure-function changes in the mitochondrial interactome with age"},{"funder_name":"NIA NIH HHS","grant_id":"T32 AG066574","title":null},{"funder_name":"NIAMS NIH HHS","grant_id":"P30 AR074990","title":null},{"funder_name":"NIA NIH HHS","grant_id":"P01 AG001751","title":null},{"funder_name":"NIA NIH HHS","grant_id":"R56 AG070096","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"P30 DK017047","title":null}],"total_grants":9,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2023,"count":2}],"oa_status":"green","license":"cc-by-nc-nd","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2023/02/03/2023.02.01.525989.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2023/02/03/2023.02.01.525989.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2023.02.01.525989","host_type":"publisher"},{"url":"http://dx.doi.org/10.1101/2023.02.01.525989","host_type":"repository"},{"url":"https://pubmed.ncbi.nlm.nih.gov/36778398","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9915686","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9915686/pdf/nihpp-2023.02.01.525989v1.pdf","host_type":"repository"},{"url":"https://doi.org/10.1101/2023.02.01.525989","host_type":""}],"fields_of_study":["Mitochondrial Function and Pathology","Sirtuins and Resveratrol in Medicine","Amyotrophic Lateral Sclerosis Research","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":[],"keywords":["Adenine nucleotide translocator","ATP–ADP translocase","ANT","Mitochondrion","Adenine nucleotide","Adenosine diphosphate","Voltage-dependent anion channel","Biochemistry","Nicotinamide adenine dinucleotide","Biology","ATP synthase","Adenosine triphosphate","NAD+ kinase","Inner mitochondrial membrane","Nucleotide","Enzyme","Platelet","Bacterial outer membrane","Article"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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