{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:18:30Z","timestamp":1774621110150,"version":"3.50.1"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T00:00:00Z","timestamp":1771632000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":34,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100009594","name":"University of P\u00e9cs","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009594","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>PGM1-congenital disorder of glycosylation (PGM1-CDG) is frequently associated with cardiomyopathy. Although galactose therapy corrects glycosylation defects, cardiac dysfunction typically persists, suggesting a glycosylation-independent mechanism. Recent evidence of mitochondrial abnormalities in PGM1-deficient human and murine heart, together with the association of PGM1 with the Z-disk protein LDB3 (ZASP\/Cypher), suggests a critical role for PGM1 in cardiomyocyte structural and energetic homeostasis. We hypothesized that PGM1-related cardiomyopathy arises from a glycosylation-independent disruption of Z-disk\u2013mitochondrial coupling driven by loss of PGM1\u2013LDB3 interactions, resulting in mitochondrial energy failure and impaired contractile function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Induced pluripotent stem cell\u2013derived cardiomyocytes (iCMs) were generated from PGM1-deficient patient fibroblasts. Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis were performed to assess functional and molecular changes. Key findings were validated using tracer metabolomics and mitochondrial respiration assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PGM1-deficient iCMs exhibited reduced beating frequency, impaired contractility, and prolonged contraction kinetics. Proteomic analyses revealed depletion of Z-disk components, including LDB3. AlphaFold3 structural modeling predicted a direct interaction between PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed in vitro. In addition, mitochondrial proteins were severely depleted, prompting us to investigate mitochondrial function. Functional validation confirmed extensive metabolic rewiring, energy depletion, and severely impaired mitochondrial respiration. Finally, the in silico drug repurposing identified possible therapeutic options that could target PGM1-deficient cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data suggests PGM1 is key regulator of cardiomyocyte function, linking sarcomeric Z-disk integrity with mitochondrial metabolism. These mechanistic insights offer a foundation for developing targeted therapies for PGM1-CDG and potentially other cardiomyopathies involving Z-disk dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-07808-9","type":"journal-article","created":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T13:35:10Z","timestamp":1771680910000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes"],"prefix":"10.1186","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8190-7736","authenticated-orcid":false,"given":"Silvia","family":"Radenkovic","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graeme","family":"Preston","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rohit","family":"Budhraja","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irena","family":"Muffels","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Ligezka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan P.","family":"Staff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ron","family":"Hrstka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bijina","family":"Balakrishnan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rameen","family":"Shah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanne","family":"Verberkmoes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ibrahim","family":"Shammas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inez","family":"Bosnyak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle M.","family":"Stiers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kent","family":"Lai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lesa J.","family":"Beamer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akhilesh","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Morava","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamas","family":"Kozicz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,21]]},"reference":[{"key":"7808_CR1","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1002\/jimd.12286","volume":"44","author":"R Altassan","year":"2021","unstructured":"Altassan R, Radenkovic S, Edmondson AC, et al. International consensus guidelines for phosphoglucomutase 1 deficiency (<\u2009scp>PGM1-CDG): Diagnosis, follow\u2010up, and management. J Inherit Metab Dis. 2021;44:148\u201363. https:\/\/doi.org\/10.1002\/jimd.12286.","journal-title":"J Inherit Metab Dis"},{"key":"7808_CR2","doi-asserted-by":"publisher","unstructured":"Fernlund E, Andersson O, Elleg\u00e5rd R, et al. The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood. Forensic Sci Int Genet. 2019;43. https:\/\/doi.org\/10.1016\/j.fsigen.2019.06.012.","DOI":"10.1016\/j.fsigen.2019.06.012"},{"key":"7808_CR3","doi-asserted-by":"publisher","unstructured":"Radenkovic S, Johnsen C, Schulze A, et al. Novel insights into the phenotype and long-term D-gal treatment in PGM1-CDG: a case series. Therapeutic Adv Rare Disease. 2023;4. https:\/\/doi.org\/10.1177\/26330040221150269.","DOI":"10.1177\/26330040221150269"},{"key":"7808_CR4","doi-asserted-by":"publisher","first-page":"108513","DOI":"10.1016\/j.ymgme.2024.108513","volume":"142","author":"R Zemet","year":"2024","unstructured":"Zemet R, Hope KD, Edmondson AC, et al. Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: recommendations for baseline screening and follow-up evaluation. Mol Genet Metab. 2024;142:108513. https:\/\/doi.org\/10.1016\/j.ymgme.2024.108513.","journal-title":"Mol Genet Metab"},{"key":"7808_CR5","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/j.ajhg.2019.03.003","volume":"104","author":"S Radenkovic","year":"2019","unstructured":"Radenkovic S, Bird MJ, Emmerzaal TL, et al. The metabolic map into the pathomechanism and treatment of PGM1-CDG. Am J Hum Genet. 2019;104:835\u201346. https:\/\/doi.org\/10.1016\/j.ajhg.2019.03.003.","journal-title":"Am J Hum Genet"},{"key":"7808_CR6","unstructured":"K\u00fc\u00e7\u00fck\u00e7ongar A, T\u00fcmer L, S\u00fcheyl Ezg\u00fc F, et al. A case with rare type of congenital disorder of glycosylation: PGM1-CDG. 2015;26."},{"key":"7808_CR7","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1002\/jmd2.12177","volume":"57","author":"SE Donoghue","year":"2021","unstructured":"Donoghue SE, White SM, Tan TY, et al. Galactose treatment of a PGM1 patient presenting with restrictive cardiomyopathy. JIMD Rep. 2021;57:29\u201337. https:\/\/doi.org\/10.1002\/jmd2.12177.","journal-title":"JIMD Rep"},{"key":"7808_CR8","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.nmd.2017.01.014","volume":"27","author":"NC Voermans","year":"2017","unstructured":"Voermans NC, Preisler N, Madsen KL, et al. PGM1 deficiency: substrate use during exercise and effect of treatment with galactose. Neuromuscul Disord. 2017;27:370\u20136. https:\/\/doi.org\/10.1016\/j.nmd.2017.01.014.","journal-title":"Neuromuscul Disord"},{"key":"7808_CR9","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1002\/jimd.12601","volume":"46","author":"S Radenkovic","year":"2023","unstructured":"Radenkovic S, Laerdahl JK, Backe PH, et al. The role of PGM1 isoform 2 in PGM1-CDG: one step closer to genotype\u2013phenotype correlation? J Inherit Metab Dis. 2023;46:159\u201360. https:\/\/doi.org\/10.1002\/jimd.12601.","journal-title":"J Inherit Metab Dis"},{"key":"7808_CR10","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1056\/nejmoa1206605","volume":"370","author":"LC Tegtmeyer","year":"2014","unstructured":"Tegtmeyer LC, Rust S, van Scherpenzeel M, et al. Multiple phenotypes in phosphoglucomutase 1 deficiency. N Engl J Med. 2014;370:533\u201342. https:\/\/doi.org\/10.1056\/nejmoa1206605.","journal-title":"N Engl J Med"},{"key":"7808_CR11","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.ymgmr.2017.07.010","volume":"13","author":"K Nolting","year":"2017","unstructured":"Nolting K, Park JH, Tegtmeyer LC, et al. Limitations of galactose therapy in phosphoglucomutase 1 deficiency. Mol Genet Metab Rep. 2017;13:33\u201340. https:\/\/doi.org\/10.1016\/j.ymgmr.2017.07.010.","journal-title":"Mol Genet Metab Rep"},{"key":"7808_CR12","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1002\/jimd.12406","volume":"44","author":"E Perales-Clemente","year":"2021","unstructured":"Perales-Clemente E, Liedtke K, Studinski A, et al. A new D-galactose treatment monitoring index for PGM1-CDG. J Inherit Metab Dis. 2021;44:1263\u201371. https:\/\/doi.org\/10.1002\/jimd.12406.","journal-title":"J Inherit Metab Dis"},{"key":"7808_CR13","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1038\/gim.2017.41","volume":"19","author":"SYW Wong","year":"2017","unstructured":"Wong SYW, Gadomski T, Van Scherpenzeel M, et al. Oral D-galactose supplementation in PGM1-CDG. Genet Sci. 2017;19:1226\u201335. https:\/\/doi.org\/10.1038\/gim.2017.41.","journal-title":"Genet Sci"},{"key":"7808_CR14","doi-asserted-by":"publisher","unstructured":"Lam C, Scaglia F, Berry GT et al. Frontiers in congenital disorders of glycosylation consortium, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort. Mol Genet Metab. 2024;142. https:\/\/doi.org\/10.1016\/j.ymgme.2024.108509.","DOI":"10.1016\/j.ymgme.2024.108509"},{"key":"7808_CR15","doi-asserted-by":"publisher","unstructured":"Backe PH, Laerdahl JK, Kittelsen LS, et al. Structural basis for substrate and product recognition in human phosphoglucomutase-1 (PGM1) isoform 2, a member of the \u03b1-d-phosphohexomutase superfamily. Sci Rep. 2020;10. https:\/\/doi.org\/10.1038\/s41598-020-62548-0.","DOI":"10.1038\/s41598-020-62548-0"},{"key":"7808_CR16","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1093\/cvr\/cvp119","volume":"83","author":"T Arimura","year":"2009","unstructured":"Arimura T, Inagaki N, Hayashi T, et al. Impaired binding of ZASP\/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy. Cardiovasc Res. 2009;83:80\u20138. https:\/\/doi.org\/10.1093\/cvr\/cvp119.","journal-title":"Cardiovasc Res"},{"key":"7808_CR17","doi-asserted-by":"publisher","unstructured":"Pathak P, Blech-Hermoni Y, Subedi K, et al. Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKC\u03b1 and TSC2-mTOR downregulation. Commun Biol. 2021;4. https:\/\/doi.org\/10.1038\/s42003-021-01864-1.","DOI":"10.1038\/s42003-021-01864-1"},{"key":"7808_CR18","doi-asserted-by":"publisher","unstructured":"Balakrishnan B, Altassan R, Budhraja R, et al. AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase I deficiency (PGM1-CDG). Transl Res. 2023. https:\/\/doi.org\/10.1016\/j.trsl.2023.01.004.","DOI":"10.1016\/j.trsl.2023.01.004"},{"key":"7808_CR19","doi-asserted-by":"publisher","unstructured":"Radenkovic S, Budhraja R, Klein-Gunnewiek T, et al. Neural and metabolic dysregulation in PMM2-deficient human in vitro neural models. Cell Rep. 2024;43. https:\/\/doi.org\/10.1016\/j.celrep.2024.113883.","DOI":"10.1016\/j.celrep.2024.113883"},{"key":"7808_CR20","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1038\/nprot.2012.150","volume":"8","author":"X Lian","year":"2013","unstructured":"Lian X, Zhang J, Azarin SM, et al. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt\/\u03b2-catenin signaling under fully defined conditions. Nat Protoc. 2013;8:162\u201375. https:\/\/doi.org\/10.1038\/nprot.2012.150.","journal-title":"Nat Protoc"},{"key":"7808_CR21","doi-asserted-by":"publisher","unstructured":"Feyen DAM, McKeithan WL, Bruyneel AAN, et al. Metabolic maturation media improve physiological function of human iPSC-Derived cardiomyocytes. Cell Rep. 2020;32. https:\/\/doi.org\/10.1016\/j.celrep.2020.107925.","DOI":"10.1016\/j.celrep.2020.107925"},{"key":"7808_CR22","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1002\/jimd.12557","volume":"46","author":"R Budhraja","year":"2023","unstructured":"Budhraja R, Saraswat M, De Graef D, et al. N-glycoproteomics reveals distinct glycosylation alterations in NGLY1-deficient patient-derived dermal fibroblasts. J Inherit Metab Dis. 2023;46:76\u201391. https:\/\/doi.org\/10.1002\/jimd.12557.","journal-title":"J Inherit Metab Dis"},{"key":"7808_CR23","doi-asserted-by":"publisher","first-page":"D1541","DOI":"10.1093\/nar\/gkaa1011","volume":"49","author":"S Rath","year":"2021","unstructured":"Rath S, Sharma R, Gupta R, et al. MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations. Nucleic Acids Res. 2021;49:D1541\u20137. https:\/\/doi.org\/10.1093\/nar\/gkaa1011.","journal-title":"Nucleic Acids Res"},{"key":"7808_CR24","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12766","author":"M Messina","year":"2024","unstructured":"Messina M, Vaz FM, Rahman S. Mitochondrial membrane synthesis, remodelling and cellular trafficking. J Inherit Metab Dis. 2024. https:\/\/doi.org\/10.1002\/jimd.12766.","journal-title":"J Inherit Metab Dis"},{"key":"7808_CR25","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","volume":"30","author":"A Kr\u00e4mer","year":"2014","unstructured":"Kr\u00e4mer A, Green J, Pollard J, et al. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics. 2014;30:523\u201330. https:\/\/doi.org\/10.1093\/bioinformatics\/btt703.","journal-title":"Bioinformatics"},{"key":"7808_CR26","doi-asserted-by":"publisher","unstructured":"Korotkevich G, Sukhov V, Budin N, et al. Fast gene set enrichment analysis n.d. https:\/\/doi.org\/10.1101\/060012.","DOI":"10.1101\/060012"},{"key":"7808_CR27","doi-asserted-by":"publisher","unstructured":"Radenkovic S, Ligezka AN, Mokashi SS, et al. Tracer metabolomics reveals the role of aldose reductase in glycosylation. Cell Rep Med. 2023;4. https:\/\/doi.org\/10.1016\/j.xcrm.2023.101056.","DOI":"10.1016\/j.xcrm.2023.101056"},{"key":"7808_CR28","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2021.12.012","author":"S Radenkovic","year":"2022","unstructured":"Radenkovic S, Martinelli D, Zhang Y, et al. TRAPPC9-CDG: A novel congenital disorder of glycosylation with dysmorphic features and intellectual disability. Genet Sci. 2022. https:\/\/doi.org\/10.1016\/j.gim.2021.12.012.","journal-title":"Genet Sci"},{"key":"7808_CR29","doi-asserted-by":"publisher","unstructured":"De Craemer S, Driesen K, Ghesqui\u00e8re B. TraVis pies: a guide for stable isotope metabolomics interpretation using an intuitive visualization. Metabolites. 2022;12. https:\/\/doi.org\/10.3390\/metabo12070593.","DOI":"10.3390\/metabo12070593"},{"key":"7808_CR30","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1038\/s41596-022-00710-w","volume":"6","author":"Z Pang","year":"2022","unstructured":"Pang Z, Zhou G, Ewald J, et al. Using metaboanalyst 5.0 for LC\u2013HRMS spectra processing, multi-omics integration and covariate adjustment of global metabolomics data. Nat Protoc. 2022;6:743\u201360. https:\/\/doi.org\/10.1038\/s41596-022-00710-w.","journal-title":"Nat Protoc"},{"key":"7808_CR31","doi-asserted-by":"publisher","unstructured":"Ligezka AN, Budhraja R, Nishiyama Y, et al. Interplay of impaired cellular bioenergetics and autophagy in PMM2-CDG. Genes (Basel). 2023;14. https:\/\/doi.org\/10.3390\/genes14081585.","DOI":"10.3390\/genes14081585"},{"key":"7808_CR32","unstructured":"Gellerich FN, Deschauer M, Chen Y, et al. Mitochondrial respiratory rates and activities of respiratory chain complexes correlate linearly with heteroplasmy of deleted mtDNA without threshold and independently of deletion size."},{"key":"7808_CR33","doi-asserted-by":"publisher","unstructured":"Preston P G, Jacob N, Elsharkawi I, et al. Phosphodiesterase type 5 Inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations. Mol Genet Metab. 2025;146. https:\/\/doi.org\/10.1016\/j.ymgme.2025.109197.","DOI":"10.1016\/j.ymgme.2025.109197"},{"key":"7808_CR34","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","volume":"630","author":"J Abramson","year":"2024","unstructured":"Abramson J, Adler J, Dunger J, et al. Accurate structure prediction of biomolecular interactions with alphafold 3. Nature. 2024;630:493\u2013500. https:\/\/doi.org\/10.1038\/s41586-024-07487-w.","journal-title":"Nature"},{"key":"7808_CR35","doi-asserted-by":"publisher","first-page":"32010","DOI":"10.1074\/jbc.M114.597914","volume":"289","author":"Y Lee","year":"2014","unstructured":"Lee Y, Stiers KM, Kain BN, et al. Compromised catalysis and potential folding defects in in vitro studies of missense mutants associated with hereditary phosphoglucomutase 1 deficiency. J Biol Chem. 2014;289:32010\u20139. https:\/\/doi.org\/10.1074\/jbc.M114.597914.","journal-title":"J Biol Chem"},{"key":"7808_CR36","doi-asserted-by":"publisher","unstructured":"Zhou X, Wang M, Katsyv I, et al. EMUDRA: ensemble of multiple drug repositioning approaches to improve prediction accuracy https:\/\/doi.org\/10.7303\/syn11510888.","DOI":"10.7303\/syn11510888"},{"key":"7808_CR37","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.nmd.2019.01.001","volume":"29","author":"WT Tian","year":"2019","unstructured":"Tian WT, Luan XH, Zhou HY, et al. Congenital disorder of glycosylation type 1T with a novel truncated homozygous mutation in PGM1 gene and literature review. Neuromuscul Disord. 2019;29:282\u20139. https:\/\/doi.org\/10.1016\/j.nmd.2019.01.001.","journal-title":"Neuromuscul Disord"},{"key":"7808_CR38","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.jpeds.2016.04.021","volume":"175","author":"SY-W Wong","year":"2016","unstructured":"Wong SY-W, Beamer LJ, Gadomski T, et al. Defining the phenotype and assessing severity in Phosphoglucomutase-1 deficiency. J Pediatr. 2016;175:130\u2013e1368. https:\/\/doi.org\/10.1016\/j.jpeds.2016.04.021.","journal-title":"J Pediatr"},{"key":"7808_CR39","doi-asserted-by":"publisher","unstructured":"Fuerstenau-Sharp M, Zimmermann ME, Stark K, et al. Generation of highly purified human cardiomyocytes from peripheral blood mononuclear cell-derived induced pluripotent stem cells. PLoS ONE. 2015;10. https:\/\/doi.org\/10.1371\/journal.pone.0126596.","DOI":"10.1371\/journal.pone.0126596"},{"key":"7808_CR40","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.scr.2009.11.004","volume":"4","author":"SR Braam","year":"2010","unstructured":"Braam SR, Tertoolen L, van de Stolpe A, et al. Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. Stem Cell Res. 2010;4:107\u201316. https:\/\/doi.org\/10.1016\/j.scr.2009.11.004.","journal-title":"Stem Cell Res"},{"key":"7808_CR41","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1016\/j.bbrc.2017.01.151","volume":"497","author":"LGJ Tertoolen","year":"2018","unstructured":"Tertoolen LGJ, Braam SR, van Meer BJ, et al. Interpretation of field potentials measured on a multi electrode array in Pharmacological toxicity screening on primary and human pluripotent stem cell-derived cardiomyocytes. Biochem Biophys Res Commun. 2018;497:1135\u201341. https:\/\/doi.org\/10.1016\/j.bbrc.2017.01.151.","journal-title":"Biochem Biophys Res Commun"},{"key":"7808_CR42","doi-asserted-by":"publisher","first-page":"29403","DOI":"10.1074\/jbc.M113.470708","volume":"288","author":"C Lin","year":"2013","unstructured":"Lin C, Guo X, Lange S, et al. Cypher\/ZASP is a novel a-kinase anchoring protein. J Biol Chem. 2013;288:29403\u201313. https:\/\/doi.org\/10.1074\/jbc.M113.470708.","journal-title":"J Biol Chem"},{"key":"7808_CR43","doi-asserted-by":"publisher","unstructured":"Katti P, Hall AS, Parry HA, et al. Mitochondrial network configuration influences sarcomere and myosin filament structure in striated muscles. Nat Commun. 2022;13. https:\/\/doi.org\/10.1038\/s41467-022-33678-y.","DOI":"10.1038\/s41467-022-33678-y"},{"key":"7808_CR44","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1002\/cphy.c160033","volume":"7","author":"CA Henderson","year":"2017","unstructured":"Henderson CA, Gomez CG, Novak SM, et al. Overview of the muscle cytoskeleton. Compr Physiol. 2017;7:891\u2013944. https:\/\/doi.org\/10.1002\/cphy.c160033.","journal-title":"Compr Physiol"},{"key":"7808_CR45","doi-asserted-by":"publisher","unstructured":"Solomon T, Rajendran M, Rostovtseva T, et al. How cytoskeletal proteins regulate mitochondrial energetics in cell physiology and diseases. Philos Trans R Soc Lond B Biol Sci. 2022;377. https:\/\/doi.org\/10.1098\/rstb.2021.0324.","DOI":"10.1098\/rstb.2021.0324"},{"key":"7808_CR46","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1093\/eurheartj\/ehad028","volume":"44","author":"EE Nollet","year":"2023","unstructured":"Nollet EE, Duursma I, Rozenbaum A, et al. Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration. Eur Heart J. 2023;44:1170\u201385. https:\/\/doi.org\/10.1093\/eurheartj\/ehad028.","journal-title":"Eur Heart J"},{"key":"7808_CR47","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1016\/j.nmd.2008.06.367","volume":"18","author":"KG Claeys","year":"2008","unstructured":"Claeys KG, Fardeau M, Schr\u00f6der R, et al. Electron microscopy in myofibrillar myopathies reveals clues to the mutated gene. Neuromuscul Disord. 2008;18:656\u201366. https:\/\/doi.org\/10.1016\/j.nmd.2008.06.367.","journal-title":"Neuromuscul Disord"},{"key":"7808_CR48","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1111\/ene.12814","volume":"22","author":"S Jackson","year":"2015","unstructured":"Jackson S, Schaefer J, Meinhardt M, et al. Mitochondrial abnormalities in the myofibrillar myopathies. Eur J Neurol. 2015;22:1429\u201335. https:\/\/doi.org\/10.1111\/ene.12814.","journal-title":"Eur J Neurol"},{"key":"7808_CR49","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1002\/ana.20376","volume":"57","author":"D Selcen","year":"2005","unstructured":"Selcen D, Engel AG. Mutations in ZASP define a novel form of muscular dystrophy in humans. Ann Neurol. 2005;57:269\u201376. https:\/\/doi.org\/10.1002\/ana.20376.","journal-title":"Ann Neurol"},{"key":"7808_CR50","doi-asserted-by":"publisher","unstructured":"Walker EM, Pearson GL, Lawlor N et al. Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues. Science (1979). 2025. https:\/\/doi.org\/10.1126\/science.adf.","DOI":"10.1126\/science.adf"},{"key":"7808_CR51","doi-asserted-by":"publisher","unstructured":"Mootha VK, Lindgren CM, Eriksson K.-F, et al. PGC-1\u03b1-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34(3):267\u201373. https:\/\/doi.org\/10.1038\/ng1180. PMID: 12808457.","DOI":"10.1038\/ng1180"},{"key":"7808_CR52","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.cell.2020.02.051","volume":"181","author":"OM Russell","year":"2020","unstructured":"Russell OM, Gorman GS, Lightowlers RN, et al. Mitochondrial diseases: hope for the future. Cell. 2020;181:168\u201388. https:\/\/doi.org\/10.1016\/j.cell.2020.02.051.","journal-title":"Cell"},{"key":"7808_CR53","doi-asserted-by":"publisher","unstructured":"Conte F, Ashikov A, Mijdam R, et al. In vitro skeletal muscle model of PGM1 deficiency reveals altered energy homeostasis. Int J Mol Sci. 2023;24. https:\/\/doi.org\/10.3390\/ijms24098247.","DOI":"10.3390\/ijms24098247"},{"key":"7808_CR54","doi-asserted-by":"publisher","unstructured":"Ramaccini D, Montoya-Uribe V, Aan FJ, et al. Mitochondrial function and dysfunction in dilated cardiomyopathy. Front Cell Dev Biol. 2021;8. https:\/\/doi.org\/10.3389\/fcell.2020.624216.","DOI":"10.3389\/fcell.2020.624216"},{"key":"7808_CR55","doi-asserted-by":"publisher","first-page":"3716","DOI":"10.1172\/JCI120849","volume":"128","author":"B Zhou","year":"2018","unstructured":"Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest. 2018;128:3716\u201326. https:\/\/doi.org\/10.1172\/JCI120849.","journal-title":"J Clin Invest"},{"key":"7808_CR56","doi-asserted-by":"publisher","first-page":"134","DOI":"10.5414\/NP300693","volume":"33","author":"PR Joshi","year":"2014","unstructured":"Joshi PR, Hauburger A, Kley R, et al. Mitochondrial abnormalities in myofibrillar myopathies. Clin Neuropathol. 2014;33:134\u201342. https:\/\/doi.org\/10.5414\/NP300693.","journal-title":"Clin Neuropathol"},{"key":"7808_CR57","doi-asserted-by":"publisher","unstructured":"Dong H, Tsai SY. Mitochondrial properties in skeletal muscle fiber. Cells. 2023;12. https:\/\/doi.org\/10.3390\/cells12172183.","DOI":"10.3390\/cells12172183"},{"key":"7808_CR58","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1161\/CIRCRESAHA.120.317685","volume":"128","author":"AR Perestrelo","year":"2021","unstructured":"Perestrelo AR, Silva AC, Oliver-De La Cruz J, et al. Multiscale analysis of extracellular matrix remodeling in the failing heart. Circ Res. 2021;128:24\u201338. https:\/\/doi.org\/10.1161\/CIRCRESAHA.120.317685.","journal-title":"Circ Res"},{"key":"7808_CR59","doi-asserted-by":"publisher","unstructured":"Silva AC, Pereira C, Fonseca ACRG et al. Bearing my heart: the role of extracellular matrix on cardiac development, homeostasis, and injury response. Front Cell Dev Biol. 2021;8. https:\/\/doi.org\/10.3389\/fcell.2020.621644.","DOI":"10.3389\/fcell.2020.621644"},{"key":"7808_CR60","doi-asserted-by":"publisher","unstructured":"Werbner B, Tavakoli-Rouzbehani OM, Fatahian AN, et al. The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure. J Cardiovasc Aging. 2023;3. https:\/\/doi.org\/10.20517\/jca.2022.42.","DOI":"10.20517\/jca.2022.42"},{"key":"7808_CR61","doi-asserted-by":"publisher","unstructured":"Radenkovic S, Adant I, Bird MJ, et al. Complex metabolomic changes in a combined defect of glycosylation and oxidative phosphorylation in a patient with pathogenic variants in PGM1 and NDUFA13. Cells. 2025;14. https:\/\/doi.org\/10.3390\/cells14090638.","DOI":"10.3390\/cells14090638"},{"key":"7808_CR62","doi-asserted-by":"publisher","first-page":"5345","DOI":"10.1002\/cphy.c230011","volume":"14","author":"R Lopez-Schenk","year":"2024","unstructured":"Lopez-Schenk R, Collins NL, Schenk NA, et al. Integrated functions of cardiac Energetics, Mechanics, and purine nucleotide metabolism. Compr Physiol. 2024;14:5345\u201369. https:\/\/doi.org\/10.1002\/cphy.c230011.","journal-title":"Compr Physiol"},{"key":"7808_CR63","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-024-00505-0","author":"JJ Hartman","year":"2024","unstructured":"Hartman JJ, Hwee DT, Robert-Paganin J, et al. Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy. Nat Cardiovasc Res. 2024. https:\/\/doi.org\/10.1038\/s44161-024-00505-0.","journal-title":"Nat Cardiovasc Res"},{"key":"7808_CR64","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1081\/NCN-200027545","volume":"23","author":"N Gattermann","year":"2004","unstructured":"Gattermann N, Dadak M, Hofhaus G, et al. Severe impairment of nucleotide synthesis through Inhibition of mitochondrial respiration. Nucleosides Nucleotides Nucleic Acids. 2004;23:1275\u20139. https:\/\/doi.org\/10.1081\/NCN-200027545.","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"7808_CR65","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2024.05.014","author":"Z Wu","year":"2024","unstructured":"Wu Z, Bezwada D, Cai F, et al. Electron transport chain Inhibition increases cellular dependence on purine transport and salvage. Cell Metab. 2024. https:\/\/doi.org\/10.1016\/j.cmet.2024.05.014.","journal-title":"Cell Metab"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-026-07808-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-026-07808-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-026-07808-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T13:16:45Z","timestamp":1774617405000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12967-026-07808-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,21]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["7808"],"URL":"https:\/\/doi.org\/10.1186\/s12967-026-07808-9","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,21]]},"assertion":[{"value":"9 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Informed research consent was obtained from all patients included in this study. Deidentified, residual samples from PGM1-CDG affected individual were used to create hiPSCs. hiPSC cell lines were derived from fibroblasts previously collected as part of clinical management and evaluation and stored in the Frontiers of Congenital Disorders of Glycosylation (FCDGC) biobank at Mayo Clinic (Mayo Clinic IRB: 16-004682) in accordance with the declaration of Helsinki. Additional healthy fibroblasts were obtained from Coriell institute (GM01651, GM08399). Two hiPSC cell lines (1363, 8858) were a gift from Dr. Sergiu Pasca and previously reported [20]. Demographic and genetic information of the PGM1-CDG individuals whose cell lines were used is given in Table\n                      \n                      .","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Authors have no conflicts of interest to declare.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"430"}}