Cellular Protein Quality Control in Diabetic Cardiomyopathy: From Bench to Bedside

Abstract

Heart failure is a serious comorbidity and the most common cause of mortality in diabetes patients. Diabetic cardiomyopathy (DCM) features impaired cellular structure and function, culminating in heart failure; however, there is a dearth of specific clinical therapy for treating DCM. Protein homeostasis is pivotal for the maintenance of cellular viability under physiological and pathological conditions, particularly in the irreplaceable cardiomyocytes; therefore, it is tightly regulated by a protein quality control (PQC) system. Three evolutionarily conserved molecular processes, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and autophagy, enhance protein turnover and preserve protein homeostasis by suppressing protein translation, degrading misfolded or unfolded proteins in cytosol or organelles, disposing of damaged and toxic proteins, recycling essential amino acids, and eliminating insoluble protein aggregates. In response to increased cellular protein demand under pathological insults, including the diabetic condition, a coordinated PQC system retains cardiac protein homeostasis and heart performance, on the contrary, inappropriate PQC function exaggerates cardiac proteotoxicity with subsequent heart dysfunction. Further investigation of the PQC mechanisms in diabetes propels a more comprehensive understanding of the molecular pathogenesis of DCM and opens new prospective treatment strategies for heart disease and heart failure in diabetes patients. In this review, the function and regulation of cardiac PQC machinery in diabetes mellitus, and the therapeutic potential for the diabetic heart are discussed.

Kai-Xin-San protects against mitochondrial dysfunction in Alzheimer’s disease through SIRT3/NLRP3 pathway

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Multi-organ FGF21-FGFR1 signaling in metabolic health and disease

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Role of BAG5 in Protein Quality Control: Double-Edged Sword?

“…Impairment of cellular PQC and accumulation of protein aggregates with faulty subcellular organelles leads to the generation of oxidative stress, inflammation, and cell death ( Li et al, 2021 ). These modifications are known to be associated with the impairment of several organ functions and the development of several life-threatening diseases including, CVD, neurological disorders, and premature aging ( Gong et al, 2016 ; Kaur et al, 2020 ). This review will discuss the evolving role of co-chaperone Bcl-2 associated anthanogene protein (BAG5) in UPS, autophagy, mitophagy, oxidative stress, metabolism, and its association with CVDs, Alzheimer’s disease, and Parkinson’s disease.…”