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. 2023 Jul;238(3):e13975.
doi: 10.1111/apha.13975. Epub 2023 Apr 30.

L-carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing PINK1-Parkin-dependent mitophagy through the CPT1a-PHB2-PARL pathways

Su Li  1   2   3 , Muyin Liu  1 , Jinxiang Chen  1 , Yuqiong Chen  4 , Ming Yin  1 , You Zhou  1   2   3 , Qiyu Li  1 , Fei Xu  1 , Youran Li  1 , Xiaopei Yan  4 , Yan Xia  1   2   3 , Ao Chen  1   2   3 , Danbo Lu  1   2   3 , Chenguang Li  1   2   3 , Li Shen  1   2   3 , Zhangwei Chen  1   2   3 , Juying Qian  1   2   3 , Junbo Ge  1   2   3
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L-carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing PINK1-Parkin-dependent mitophagy through the CPT1a-PHB2-PARL pathways

Su Li et al. Acta Physiol (Oxf). 2023 Jul.

Abstract

Aim: To explore the beneficial effects of L-carnitine on cardiac microvascular dysfunction in diabetic cardiomyopathy from the perspectives of mitophagy and mitochondrial integrity.

Methods: Male db/db and db/m mice were randomly assigned to groups and were treated with L-carnitine or a solvent for 24 weeks. Endothelium-specific PARL overexpression was attained via adeno-associated virus serotype 9 (AAV9) transfection. Adenovirus (ADV) vectors overexpressing wild-type 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.

Results: L-carnitine 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-Parkin-dependent mitophagy was suppressed in endothelial cells suffering from diabetic injury, and these effects were largely alleviated by L-carnitine through the inhibition of PARL detachment from PHB2. Moreover, CPT1a modulated the PHB2-PARL interaction by directly binding to PHB2. The increase in CPT1a activity induced by L-carnitine or amino acid mutation (M593S) enhanced the PHB2-PARL interaction, thereby improving mitophagy and mitochondrial function. In contrast, PARL overexpression inhibited mitophagy and abolished all the beneficial effects of L-carnitine on mitochondrial integrity and cardiac microvascular function.

Conclusion: L-carnitine treatment enhanced PINK1-Parkin-dependent mitophagy by maintaining the PHB2-PARL interaction via CPT1a, thereby reversing mitochondrial dysfunction and cardiac microvascular injury in diabetic cardiomyopathy.

Keywords: L-carnitine; PARL; PHB2; cardiac microvascular dysfunction; diabetes mellitus; mitophagy.

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