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

Oct 2, 2025Journal of advanced research

How cell death, gene regulation, and daily body clocks interact to control mitochondrial health in diabetic heart disease

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Abstract

Mitochondrial dysfunction is identified as a key feature of diabetic cardiomyopathy.

Disruptions in mitochondrial quality control are associated with the initiation and progression of diabetic cardiomyopathy.
Imbalanced mitochondrial fission and fusion dynamics, reduced mitochondrial production, and impaired removal of damaged mitochondria are observed in this condition.
Altered calcium levels, increased susceptibility to ferroptosis, and loss of protein regulation contribute to mitochondrial decline.
Mechanistic interactions among these processes may worsen mitochondrial health and lead to heart injury.
Recent therapeutic strategies targeting mitochondrial quality control include natural compounds and antidiabetic agents, though challenges remain for clinical application.

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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 Cahomeostasis, 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. 2+

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

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