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

Su Li; Muyin Liu; Jinxiang Chen; Yuqiong Chen; Ming Yin; You Zhou; Qiyu Li; Fei Xu; Youran Li; Xiaopei Yan; Yan Xia; Ao Chen; Danbo Lu; Chenguang Li; Li Shen; Zhangwei Chen; Juying Qian; Junbo Ge

doi:10.1111/apha.13975

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

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

Authors

Su Li^{1

2

3}, Muyin Liu¹, Jinxiang Chen¹, Yuqiong Chen⁴, Ming Yin¹, You Zhou^{1

2

3}, Qiyu Li¹, Fei Xu¹, Youran Li¹, Xiaopei Yan⁴, 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}

Affiliations

¹ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
² National Clinical Research Center for Interventional Medicine, Shanghai, China.
³ Shanghai Clinical Research Center for Interventional Medicine, Shanghai, China.
⁴ Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.

PMID: 37042471
DOI: 10.1111/apha.13975

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carnitine / pharmacology
Diabetes Mellitus*
Diabetic Cardiomyopathies* / drug therapy
Endothelial Cells / metabolism
Male
Mice
Mitophagy
Protein Kinases / genetics
Protein Kinases / metabolism
Protein Kinases / pharmacology
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Ubiquitin-Protein Ligases / pharmacology

Substances

Carnitine
Protein Kinases
Ubiquitin-Protein Ligases