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More recently, <jats:styled-content style=\"fixed-case\">mtHKII<\/jats:styled-content> has emerged as a powerful protector against cardiac cell death. <jats:styled-content style=\"fixed-case\">mtHKII<\/jats:styled-content> protects against ischaemia\u2010reperfusion (<jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content>) injury in skeletal muscle and heart, attenuates cardiac hypertrophy and remodelling, and is one of the major end\u2010effectors through which ischaemic preconditioning protects against myocardial <jats:styled-content style=\"fixed-case\">IR<\/jats:styled-content> injury. Mechanisms of <jats:styled-content style=\"fixed-case\">mtHKII<\/jats:styled-content> cardioprotection against reperfusion injury entail the maintenance of regulated outer mitochondrial membrane (<jats:styled-content style=\"fixed-case\">OMM<\/jats:styled-content>) permeability during ischaemia and reperfusion resulting in stabilization of mitochondrial membrane potential, the prevention of <jats:styled-content style=\"fixed-case\">OMM<\/jats:styled-content> breakage and cytochrome <jats:styled-content style=\"fixed-case\">C<\/jats:styled-content> release, and reduced reactive oxygen species production. Increasing <jats:styled-content style=\"fixed-case\">mtHK<\/jats:styled-content> may also have important metabolic consequences, such as improvement of glucose\u2010induced insulin release, prevention of acidosis through enhanced coupling of glycolysis and glucose oxidation, and inhibition of fatty acid oxidation. Deficiencies in expression and distorted cellular signalling of <jats:styled-content style=\"fixed-case\">HKII<\/jats:styled-content> may contribute to the altered sensitivity of diabetes to cardiac ischaemic diseases. The interaction of <jats:styled-content style=\"fixed-case\">HKII<\/jats:styled-content> with the mitochondrion constitutes a powerful endogenous molecular mechanism to protect against cell death in almost all cell types examined (neurons, tumours, kidney, lung, skeletal muscle, heart). The challenge now is to harness <jats:styled-content style=\"fixed-case\">mtHKII<\/jats:styled-content> in the treatment of infarction, stroke, elective surgery and transplantation. Remote ischaemic preconditioning, metformin administration and <jats:styled-content style=\"fixed-case\">miR<\/jats:styled-content>\u2010155\/<jats:styled-content style=\"fixed-case\">miR<\/jats:styled-content>\u2010144 manipulations are potential means of doing just that.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury &amp; Beyond. To view the other articles in this issue visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/dx.doi.org\/10.1111\/bph.2014.171.issue-8\">http:\/\/dx.doi.org\/10.1111\/bph.2014.171.issue\u20108<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12363","type":"journal-article","created":{"date-parts":[[2013,8,30]],"date-time":"2013-08-30T09:53:56Z","timestamp":1377856436000},"page":"2067-2079","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":104,"title":["Targeting hexokinase <scp>II<\/scp> to mitochondria to modulate energy metabolism and reduce ischaemia\u2010reperfusion injury in heart"],"prefix":"10.1111","volume":"171","author":[{"given":"Rianne","family":"Nederlof","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Intensive Care and Anesthesiology Department of Anesthesiology University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Otto","family":"Eerbeek","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Embryology and Physiology Academic Medical Center University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus W","family":"Hollmann","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Intensive Care and Anesthesiology Department of Anesthesiology University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Southworth","sequence":"additional","affiliation":[{"name":"Department of Imaging Chemistry and Biology Division of Imaging Sciences and Biomedical Engineering King's College  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coert J","family":"Zuurbier","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Intensive Care and Anesthesiology Department of Anesthesiology University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,3,28]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/83.3.273"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00410.2001"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.011387"},{"key":"e_1_2_12_5_1","doi-asserted-by":"crossref","first-page":"8834","DOI":"10.1016\/S0021-9258(19)50355-6","article-title":"Modulation of the mitochondrial cyclosporin A\u2010sensitive permeability transition pore by the proton electrochemical gradient","volume":"267","author":"Bernardi P","year":"1992","journal-title":"J Biol Chem"},{"key":"e_1_2_12_6_1","first-page":"55","volume-title":"Current Topics in Cellular Regulation","author":"Bessmann SP","year":"1980"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2736(97)00175-2"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-007-0691-y"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2471"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.10.020"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02027312"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2005.09.007"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110927200"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.74.9.3735"},{"key":"e_1_2_12_15_1","doi-asserted-by":"crossref","first-page":"8699","DOI":"10.1016\/S0021-9258(19)68900-3","article-title":"Energy metabolism of tumor cells. 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