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

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.

Elucidating molecular mechanisms that alleviate cardiac microvascular dysfunction in diabetes: The potential benefit of targeting mitophagy and mitochondrial integrity

“…They also showed that enhanced lipid metabolism via CPT1a activity reinforced the PHB2-PARL interaction and that overexpression of PARL abolished the protective effects of LC on cardiac microvascular function. 1 Taken together, these data indicate that PARL detaches from PHB2 and thereby exacerbates CMD in diabetes mellitus by suppressing PINK-PRKN-dependent mitophagy. LC treatment subsequently alleviates this dysfunction by enhancing the PHB2-PARL interaction (via CPT1a activation), resulting in enhanced mitophagy and cardiac microvascular protection.…”

“…These proposed mechanisms are well-summarized in Figure 8H of the manuscript. 1 Overall, these results from Li and colleagues are compelling and help establish a potential mechanistic pathway for how LC impacts mitophagy and CMD. These findings also carry potential translational value given that LC therapy has demonstrated beneficial effects on glucose metabolism in humans with diabetes.…”

“…In this issue of Acta Physiologica, Li et al report that L-carnitine (LC) therapy reversed mitochondrial dysfunction and repaired cardiac microvascular injury in diabetic cardiomyopathy. 1 Specifically, they describe how LC augmented PINK1-Parkin-dependent mitophagy by maintaining the PHB2-PARL interaction via CPT1 in db/db mice. 1 This is an interesting discovery that holds translational value given the growing recognition of mitophagy as a contributing factor to coronary microvascular dysfunction (CMD).…”

“…1 Specifically, they describe how LC augmented PINK1-Parkin-dependent mitophagy by maintaining the PHB2-PARL interaction via CPT1 in db/db mice. 1 This is an interesting discovery that holds translational value given the growing recognition of mitophagy as a contributing factor to coronary microvascular dysfunction (CMD). 2 Mitophagy is an autophagic response that specifically targets damaged and, therefore, potentially cytotoxic mitochondria.…”

“…LC is an amino acid derivative widely known for its involvement in the transport (via the CPT1 transporter) of long-chain fatty acids into the mitochondrial matrix and has been suggested as a potential alternative for the treatment of CMD, though underlying mechanisms for this have not been clearly defined. 1 Toward this goal, Li and colleagues aimed to clarify the potential mechanisms of LC therapy for coronary microvascular protection in diabetes mellitus, with an emphasis on mitophagy and mitochondrial integrity. Their investigation demonstrated that 24 weeks of LC treatment (dosed at 200 mg/kg/day) in db/db mice: (1) improved cardiac function by upregulating glucose and lipid metabolism and (2) improved cardiac microvascular perfusion by enhancing endothelium-dependent vasodilation.…”