Mitochondria-Endoplasmic Reticulum Contacts: The Promising Regulators in Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM), as a serious complication of diabetes, causes structural and functional abnormalities of the heart and eventually progresses to heart failure. Currently, there is no specific treatment for DCM. Studies have proved that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are key factors for the development and progression of DCM. The mitochondria-associated ER membranes (MAMs) are a unique domain formed by physical contacts between mitochondria and ER and mediate organelle communication. Under high glucose conditions, changes in the distance and composition of MAMs lead to abnormal intracellular signal transduction, which will affect the physiological function of MAMs, such as alter the Ca2+ homeostasis in cardiomyocytes, and lead to mitochondrial dysfunction and abnormal apoptosis. Therefore, the dysfunction of MAMs is closely related to the pathogenesis of DCM. In this review, we summarized the evidence for the role of MAMs in DCM and described that MAMs participated directly or indirectly in the regulation of the pathophysiological process of DCM via the regulation of Ca2+ signaling, mitochondrial dynamics, ER stress, autophagy, and inflammation. Finally, we discussed the clinical transformation prospects and technical limitations of MAMs-associated proteins (such as MFN2, FUNDC1, and GSK3β) as potential therapeutic targets for DCM.

Apelin‑13 reduces high glucose‑induced mitochondrial dysfunction in cochlear hair cells by inhibiting endoplasmic reticulum stress

“…Elucidating the pathogenesis of diabetic hearing loss based on hair cells is necessary to offer insights crucial for early diagnosis, prevention and effective management strategies. Existing research has highlighted the detrimental impact of heightened glucose or fat levels on diabetes, resulting in increased mitochondrial load and the accumulation of damaged mitochondria within cells ( 23-25 ). The present study, employing JC-1 and MitoSOX Red probes combined with ATP detection, successfully demonstrated the adverse effects of HG intervention, including diminished MMP, reduced ATP production and an increase in mtROS within HEI-OC1 cells.…”

GSK3β: A ray of hope for the treatment of diabetic kidney disease

“…However, GSK3β is also located within the mitochondria and nucleus, as well as other subcellular compartments. Mitochondrial GSK3β may be especially important in oxidative stress, energy metabolism, and mitochondria‐associated endoplasmic reticulum dysfunction 25,26 . Intranuclear GSK3β affects biological functions via recently identified epigenetic mechanisms enriched in its regulation of many transcription factors, DNA methylation, and histone modification 27 …”

Exploring the Complex Relationship between Diabetes and Cardiovascular Complications: Understanding Diabetic Cardiomyopathy and Promising Therapies

“…Along similar lines, high glucose levels act to attenuate SERCA2a function, but exendin-4 treatment prevented this reduction. These findings suggest that GLP-1 receptor activation could attenuate high glucose-induced cardiomyocyte apoptosis by mechanisms involving reduced ER stress and by improved SERCA2a activity, which further boosts the use of GLP-1 receptor-based therapies as treatments for DCM [ 43 , 132 , 133 ].…”