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Endothelium\u2010specific PARL overexpression was attained via adeno\u2010associated virus serotype 9 (AAV9) transfection. Adenovirus (ADV) vectors overexpressing wild\u2010type CPT1a, mutant CPT1a, or PARL were transfected into endothelial cells exposed to high glucose and free fatty acid (HG\/FFA) injury. Cardiac microvascular function, mitophagy, and mitochondrial function were analyzed by immunofluorescence and transmission electron microscopy. Protein expression and interactions were assessed by western blotting and immunoprecipitation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>L\u2010carnitine treatment enhanced microvascular perfusion, reinforced endothelial barrier function, repressed the endothelial inflammatory response, and maintained the microvascular structure in db\/db mice. Further results demonstrated that PINK1\u2010Parkin\u2010dependent mitophagy was suppressed in endothelial cells suffering from diabetic injury, and these effects were largely alleviated by L\u2010carnitine through the inhibition of PARL detachment from PHB2. Moreover, CPT1a modulated the PHB2\u2010PARL interaction by directly binding to PHB2. The increase in CPT1a activity induced by L\u2010carnitine or amino acid mutation (M593S) enhanced the PHB2\u2010PARL interaction, thereby improving mitophagy and mitochondrial function. In contrast, PARL overexpression inhibited mitophagy and abolished all the beneficial effects of L\u2010carnitine on mitochondrial integrity and cardiac microvascular function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>L\u2010carnitine treatment enhanced PINK1\u2010Parkin\u2010dependent mitophagy by maintaining the PHB2\u2010PARL interaction via CPT1a, thereby reversing mitochondrial dysfunction and cardiac microvascular injury in diabetic cardiomyopathy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13975","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T11:07:43Z","timestamp":1681297663000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["L\u2010carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing <scp>PINK1\u2010Parkin<\/scp>\u2010dependent mitophagy through the <scp>CPT1a\u2010PHB2\u2010PARL<\/scp> 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