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Although the mechanisms underlying cardiac ischaemia\u2013reperfusion injury have been intensively investigated, effective therapeutic strategies applicable during reperfusion to mitigate this damage have not been established yet. To obtain more insights into the mechanisms underlying ischaemia\u2013reperfusion injury, and to explore effective methods to relieve reperfusion injury, we developed a comprehensive mathematical model of ventricular myocyte, implementing excitation\u2013contraction (E\u2013C) coupling, cytosolic and mitochondrial pH regulation, pH dependence of major components of E\u2013C coupling and cellular energy metabolism, including mitochondrial oxidative phosphorylation. The mathematical model successfully reproduced experimentally observed findings on cardiac ischaemia\u2013reperfusion injury, such as intracellular and extracellular acidosis, cytosolic Na\n                      <jats:sup>+<\/jats:sup>\n                      overload, cytosolic Ca\n                      <jats:sup>2+<\/jats:sup>\n                      overload, mitochondrial dysfunction, action potential shortening and contraction failure. It was found that the reperfusion\u2010induced exacerbation of Na\n                      <jats:sup>+<\/jats:sup>\n                      <jats:sub>i<\/jats:sub>\n                      , Ca\n                      <jats:sup>2+<\/jats:sup>\n                      <jats:sub>i<\/jats:sub>\n                      overloads was mainly caused by insufficient production of NADH, which is used in mitochondrial oxidative phosphorylation to synthesize ATP for Na\n                      <jats:sup>+<\/jats:sup>\n                      \/K\n                      <jats:sup>+<\/jats:sup>\n                      pump and sarcoplasmic\/endoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      pump (SERCA) to expel accumulated cytosolic Na\n                      <jats:sup>+<\/jats:sup>\n                      and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      , respectively. It was suggested that the preservation of mitochondrial NADH production, attenuation of ATP consumption via SERCA or contraction for a short period or activation of the Na\n                      <jats:sup>+<\/jats:sup>\n                      \/K\n                      <jats:sup>+<\/jats:sup>\n                      pump during reperfusion mitigates reperfusion injury.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70736-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Experimental data on cardiac ischaemia\u2013reperfusion injury are available.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>No effective methods applicable during reperfusion were available for mitigating the injury.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We developed a comprehensive cardiomyocyte model to simulate the injury.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Na\n                            <jats:sup>+<\/jats:sup>\n                            and Ca\n                            <jats:sup>2+<\/jats:sup>\n                            overloads and contraction failure could be reproduced by the model.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            It was found that correcting ATP supply\u2013consumption imbalance during reperfusion, that is, preservation of mitochondrial NADH production, attenuation of ATP consumption or activation of the Na\n                            <jats:sup>+<\/jats:sup>\n                            \/K\n                            <jats:sup>+<\/jats:sup>\n                            pump, was effective at mitigating the injury.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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