Microtubule affinity-regulating kinase 4 exacerbates diabetic cardiomyopathy by inhibiting UNC-51-like kinase 1-mediated mitochondrial autophagy
Year: 2026
Type: article
Abstract: BACKGROUND: The incidence of diabetic cardiomyopathy (DCM) is increasing significantly as the population ages. DCM is one of the main causes of heart failure and mortality among patients with diabetes. Impaired mitophagy leads to mitochondrial dysfunction, which in turn aggravates DCM progression. Microtubule affinity-regulating kinase 4 (MARK4) is a key regulator of autophagy in adipocytes. AIM: To investigate the role of MARK4 in mitophagy in DCM. METHODS: A mouse model of type 2 DCM was developed by administration of low-dose streptozotocin (50 mg/kg) combined with a high-fat diet. After 12 weeks MARK4 expression was knocked down in the mice by injection of the adeno-associated virus AAV9 into the tail vein. Four weeks later, cardiac function and structure were evaluated by echocardiography, and blood glucose levels and body weights were recorded. Mitochondrial ultrastructure and autophagosomes were assessed using electron microscopy. Mitochondrial membrane potentials were examined using fluorescence microscopy while the MARK4 and mitophagy-associated protein levels were investigated using western blotting. The downstream factors of MARK4 were identified using RNA-seq sequencing and bioinformatics with empirical confirmation. RESULTS: upregulation of UNC-51-like kinase 1, alleviating myocardial injury in mice. This was confirmed in cell rescue experiments. Bioinformatics predicted interaction between MARK4 and the autophagy marker protein microtubule-associated protein 1 light chain 3B. This was verified using co-immunoprecipitation. CONCLUSION: Downregulation of MARK4 in DCM mice can reduce myocardial injury, protect mitochondrial function, and promote mitophagy by upregulating UNC-51-like kinase 1, protecting against cardiac damage.
Source: World Journal of Diabetes
Authors: Yi Wu, Wei-Yi Wang, Jing-Qi Zhang, Sai Wang, Zhi Zeng, Lu Fu, Bin Li
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
Awards: G1070754419, G2295955150, G2348369761, Regulation of myocardial growth and death by GSK-3, G3081755402, G3129730382, G3405322071, G3642352218, G3777667531, G4101633970, Redox regulation in aging and failing heart, G5059533426, G5103921932, Cardioprotective effects of thioredoxin 1, G5538412199, Prevention myocardial injury by inhibition of autosis, G5804956950, G5806494660, G5925465205, G6269310686, Increasing the level of arginine methylation correlates with ischemia-induced autophagy in the heart, Regulation of myocardial growth and death by autophagy, G6888827278, G7384925648, G76062032, G7689581808, G7809128723, G8430394541, G8759340591, G8842179039
OpenAlex ID: W7123698045