Reversing diastolic dysfunction in diabetes: a mitochondrial quality control-centric pharmacological approach

May 22, 2026Acta diabetologica

Improving heart relaxation problems in diabetes by targeting how cells maintain healthy energy makers

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Abstract

Diabetic cardiomyopathy (DCM) may result from disruptions in mitochondrial quality control that are associated with chronic hyperglycemia and lipid overload.

DCM is characterized by changes in heart muscle structure and function that occur independently of hypertension or other heart diseases.
Disruptions in mitochondrial homeostasis can lead to oxidative stress and impaired energy production in heart cells.
Dysregulated mitochondrial dynamics may contribute to severe outcomes such as heart cell death and heart failure.
Key regulatory processes of mitochondrial quality control include mitochondrial dynamics, selective removal of damaged mitochondria, mitochondrial growth, and stress responses.
Molecules like Drp1 and Parkin are identified as potential targets for therapies aimed at regulating mitochondrial quality control.
Challenges in applying current research findings to clinical settings arise due to differences between species and the complexity of mitochondrial quality control.

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Diabetic cardiomyopathy (DCM) is a major contributor to the cardiovascular complications associated with diabetes. This condition is characterized by structural and functional abnormalities of the myocardium that occur independently of factors such as hypertension or other established cardiac diseases. In this review, we focus on the mitochondrial quality control (MQC) system, a critical determinant in the pathogenesis of DCM. In the diabetic milieu, chronic hyperglycemia and lipid overload disrupt mitochondrial homeostasis, leading to oxidative stress, impaired energy metabolism, and dysregulated mitochondrial dynamics. These disturbances serve as precursors to severe pathological outcomes, including cardiomyocyte death, myocardial fibrosis, and the progression of heart failure. This paper systematically examines the four pillars of MQC regulation-mitochondrial dynamics, selective autophagy (mitophagy), mitochondrial biogenesis, and the mitochondrial unfolded protein response (UPRmt)-and discusses how dysregulation of these regulatory networks contributes to the development of DCM. We further explore the molecular mechanisms involving key regulators such as Drp1 and Parkin, emphasizing their potential as therapeutic targets. Although current research has identified promising strategies, including hypoglycemic agents, melatonin, and various natural compounds that modulate MQC in preclinical models, translating these findings into clinical practice remains challenging due to species differences and the inherent complexity of MQC regulation. Future research should prioritize multi-target combination therapies and personalized treatment strategies aimed at preserving mitochondrial homeostasis and delaying the progression of DCM.

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Reversing diastolic dysfunction in diabetes: a mitochondrial quality control-centric pharmacological approach

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