The role of circadian clock-controlled mitochondrial dynamics in diabetic cardiomyopathy

Abstract

Diabetes mellitus is a metabolic disease with a high prevalence worldwide, and cardiovascular complications are the leading cause of mortality in patients with diabetes. Diabetic cardiomyopathy (DCM), which is prone to heart failure with preserved ejection fraction, is defined as a cardiac dysfunction without conventional cardiac risk factors such as coronary heart disease and hypertension. Mitochondria are the centers of energy metabolism that are very important for maintaining the function of the heart. They are highly dynamic in response to environmental changes through mitochondrial dynamics. The disruption of mitochondrial dynamics is closely related to the occurrence and development of DCM. Mitochondrial dynamics are controlled by circadian clock and show oscillation rhythm. This rhythm enables mitochondria to respond to changing energy demands in different environments, but it is disordered in diabetes. In this review, we summarize the significant role of circadian clock-controlled mitochondrial dynamics in the etiology of DCM and hope to play a certain enlightening role in the treatment of DCM.

Keywords: clock circadian; diabetic cardiomyopathy; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion.

Figure 1

The process of mitochondrial dynamics. Mitochondrial fusion: MFN1 and MFN2 form homodimer or heterodimer, then alter the conformation of the HR2 region depending on GTPase, resulting in the fusion of OMM. IMM fusion is mainly orchestrated by OPA1. The L-OPA1 interacts with lid cardiolipin and facilitates the fusion of the IMM. The S-OPA1 interacts with L-OPA1 and promotes IMM fusion. Mitochondrial fission: The dephosphorylated DRP1 is recruited at the mitochondrial membrane by its receptors, mainly including FIS and MFF. MID49 and MID51 also recruit DRP1 when the MFF/FIS1 is not available. Recruited DRP1 combined with the receptor, forming a ring-like structure to shear the mitochondria and promote the completion of mitochondrial fission. Mitophagy: Damaged mitochondria are degraded by autophagosomes through PINK1/Parkin and BNIP3 pathways.

Figure 2

The transcription-translation feedback loop (TTFL) of the circadian clock. The main TTFL is driven by BMAL1-CLOCK dimer combined with E-box, and their negative regulators include the period (PER), cryptochrome (CRY), casein kinases, and phosphatases, which form a heterodimer in the cytoplasm and translocate into the nucleus to inhibit the transcription of CLOCK-BMAL1. In the second TTFL, REV-ERBα/β and RORα are also activated by CLOCK-BMAL1. REV-ERBα/β negatively regulates BMAL1 transcription, but RORαpositively regulates BMAL1 transcription.

Figure 3

The relevant mechanisms by which circadian clock controls mitochondrial dynamics. The circadian clock regulates mitochondrial dynamics through influencing the molecules involved in it, including calcineurin, PUF60, AMPK, SIRT1 and SIRT3.

Figure 4

The role of clock-controlled mitochondrial dynamics in DCM. The disturbed clock-controlled mitochondrial dynamics may affect insulin signaling, lipid metabolism, mitochondrial ROS production, Ca²⁺ processing, MMP, mitophagy and ER stress, resulting in lipid accumulation, inflammation, myocardial fibrosis, cardiac hypertrophy, cardiac apoptosis and microvascular damage, and ultimately participate in the development of DCM.