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

In this issue of Acta Physiologica, Li et al. report that Lcarnitine (LC) therapy reversed mitochondrial dysfunction and repaired cardiac microvascular injury in diabetic cardiomyopathy.1 Specifically, they describe how LC augmented PINK1Parkindependent mitophagy by maintaining the PHB2PARL 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.3 Interestingly, a recent in vitro study of human umbilical vein endothelial cells reported that mitophagy alleviated ischemia/ reperfusioninduced microvascular damage by improving mitochondrial quality control,4 suggesting that mitophagy may represent a key quality control pathway in the microcirculation. Along these lines, emerging clinical evidence now highlights two potentially interrelated findings: (1) mitochondrial dysfunction is common in people with diabetes5 and may be the primary cause of CMD4 and (2) mitochondrial dysfunction and CMD are each linked to heart failure with preserved ejection fraction, which is the most common heart failure phenotype in people with diabetes.6 While these observations are intriguing, the field is currently limited by a lack of clear mechanistic insight that may inform targeted therapies aimed at alleviating both mitochondrial dysfunction and CMD. LC is an amino acid derivative widely known for its involvement in the transport (via the CPT1 transporter) of longchain 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 endotheliumdependent vasodilation. Moreover, they used in vitro studies of human cardiac microvascular endothelial cells to demonstrate that LC: (1) improved mitophagy and mitochondrial integrity via the PINK1Parkin pathway; (2) reduced apoptosis by improving autophagy under conditions of high glucose and/or free fatty acid stress; (3) enhanced mitophagy via the PHB2PARL pathway in the context of high glucose/ free fatty acidinduced injury. They also showed that enhanced lipid metabolism via CPT1a activity reinforced the PHB2PARL 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 PINKPRKNdependent mitophagy. LC treatment subsequently alleviates this dysfunction by enhancing the PHB2PARL interaction (via CPT1a activation), resulting in enhanced mitophagy and cardiac microvascular protection. These proposed mechanisms are wellsummarized 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.7 However, this potential value must be tempered by conflicting evidence from clinical trials investigating the effects of LC on cardiovascular