REVIEW article
Front. Endocrinol.
Sec. Diabetes: Molecular Mechanisms
This article is part of the Research TopicThe Complex Phenotype of Diabetic Cardiomyopathy: Clinical Indicators and Novel Treatment Targets – Volume IIView all 10 articles
Metabolic-Stress-Induced Mitochondrial Calcium Dysregulation: A Central Hub in Diabetic Cardiomyopathy Pathogenesis and Treatment
Provisionally accepted
- 1Zhejiang University, Hangzhou, China
- 2The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University,, Yiwu, China
- 3Corresponding Author, Department of Cardiology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
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Diabetic cardiomyopathy (DCM), as a devastating complication of diabetes mellitus (DM), arises from a complex interplay between systemic metabolic derangements and myocardial vulnerability. While hyperglycemia, lipotoxicity, and insulin resistance are established drivers of cardiac dysfunction, the precise mechanisms linking these metabolic insults to cardiac dysfunction remain elusive. Recent evidence suggests that the dysregulation of mitochondrial calcium homeostasis plays a critical role in integrating diabetic metabolic stress and cardiomyocyte fate. This review synthesizes recent advances in understanding how mitochondrial calcium mishandling—encompassing impaired uptake, excessive release, and buffering failure—orchestrates the pathological triad of bioenergetic deficit, oxidative stress, and cell death in DCM. We delve into the molecular mechanisms underpinning this dysregulation, highlighting its interplay with the diabetic metabolic milieu. Furthermore, we critically evaluate novel therapeutic strategies targeting mitochondrial calcium fluxes, including the inhibition of the mitochondrial calcium uniporter (MCU), the activation of the mitochondrial Na⁺/Ca²⁺/Li⁺ exchanger (NCLX), and the modulation of the mitochondrial permeability transition pore (mPTP), discussing their clinical translation potential and existing challenges. By reframing DCM through the lens of mitochondrial calcium homeostasis, this review not only synthesizes current knowledge but also provides a critical comparison of emerging therapeutic strategies and evaluates the formidable challenges in their clinical translation, thereby bridging the gap between endocrine metabolism and cardiac pathophysiology and offering nuanced perspectives for biomarker discovery and stage-specific interventions.
Keywords: Diabetic cardiomyopathy, mitochondrial calcium, calcium homeostasis, Mitochondrial dysfunction, Heart Failure, therapeutic targets
Received: 31 Aug 2025; Accepted: 17 Nov 2025.
Copyright: © 2025 Deng, Tayefi and Jin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yunpeng Jin, 8013013@zju.edu.cn
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