Cross-regulatory mechanisms linking ferroptosis, epigenetics, and circadian rhythm to mitochondrial quality control in diabetic cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is a distinct cardiac disorder that develops independently of coronary artery disease and hypertension. Mitochondrial dysfunction is widely recognized as a hallmark pathological feature of DCM. Effective mitochondrial quality control (MQC) is critical for preserving cardiomyocyte metabolism and contractile performance, and its disruption substantially contributes to both disease initiation and progression. We synthesize current evidence on disruptions of MQC in diabetic cardiomyopathy. The spectrum covers imbalanced fission–fusion dynamics, attenuated mitochondrial biogenesis, compromised mitophagy, disturbed Ca²⁺ homeostasis, heightened ferroptotic vulnerability, loss of proteostasis, and epigenetic dysregulation. We emphasize the intricate cross-talk among these processes, which collectively exacerbate mitochondrial deterioration and myocardial injury. Building on these mechanistic insights, we also summarize recent therapeutic advances targeting MQC, such as natural compounds, antidiabetic agents, and non-pharmacological approaches. These interventions show promise in modulating mitochondrial signaling and restoring homeostasis. Nevertheless, substantial barriers remain for clinical translation, including the limitations of existing experimental models, the low quality of supporting evidence, and pronounced inter-individual variability. Future research should focus on developing integrated, multi-target therapeutic strategies, particularly those addressing the regulatory roles of non-coding RNAs, epigenetic modifications, and post-translational protein regulation. Advancing these areas will be essential for establishing precise and effective MQC-targeted therapies in both preclinical and clinical contexts.