{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:44:06Z","timestamp":1789526646589,"version":"build-2803163510"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Res"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>DNM1L<\/jats:italic>\n                      encodes dynamin-related protein 1, which plays an important role in mitochondrial and peroxisomal division. The\n                      <jats:italic>DNM1L<\/jats:italic>\n                      mutation leads to cardiac dysfunction in patients and animal models. However, the mechanism of cardiac dysfunction caused by\n                      <jats:italic>DNM1L<\/jats:italic>\n                      mutation has not been elucidated clearly at least in the studies of human cardiomyocytes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We established human induced pluripotent stem cells (hiPSCs) from two pediatric patients with\n                      <jats:italic>DNM1L<\/jats:italic>\n                      mutation. The hiPSCs were differentiated into hiPSC-derived cardiomyocytes (hiPS-CMs). Mitochondrial morphology and function, cardiomyocyte Ca\n                      <jats:sup>2+<\/jats:sup>\n                      dynamics, and contractile and diastolic function of hiPS-CMs were analyzed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The morphology of the mitochondria was abnormally elongated in patient-derived hiPS-CMs. The mitochondrial membrane potential and oxygen consumption rate were significantly decreased, resulting in reduced ATP production. In the analysis of Ca\n                      <jats:sup>2+<\/jats:sup>\n                      dynamics, the 50% time to decay was significantly longer in patient-derived hiPS-CMs than in healthy control. High-precision live-imaging system analysis revealed that contractile and diastolic function was significantly impaired under isoproterenol stimulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>DNM1L<\/jats:italic>\n                      mutations cause mitochondrial impairment with less production of ATP in cardiomyocytes. This leads to abnormal intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      dynamics, resulting in contractile and diastolic dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Impact<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>DNM1L<\/jats:italic>\n                            mutations was identified in two pediatric patients who developed cardiac dysfunction and human induced pluripotent stem cells (hiPSCs) were established from these two patients and differentiated into hiPSC-derived cardiomyocytes (hiPS-CMs).\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>DNM1L<\/jats:italic>\n                            mutations induced abnormal mitochondrial morphology, mitochondrial dysfunction, and insufficient ATP production in hiPS-CMs. In addition, hiPS-CMs with\n                            <jats:italic>DNM1L<\/jats:italic>\n                            mutation showed abnormal Ca\n                            <jats:sup>2+<\/jats:sup>\n                            kinetics and impaired contractile and diastolic function.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            This is the first study that elucidate the mechanism of cardiac dysfunction caused by\n                            <jats:italic>DNM1L<\/jats:italic>\n                            mutations by using hiPSCs.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n     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