Β-Hydroxybutyrate inhibits centriole duplication and mitochondrial dysfunction through β-hydroxybutyrylation of ANXA11 in diabetic cardiomyopathy rats

Abstract

Background

Mitochondrial dysfunction is a major mechanism in the development of diabetic cardiomyopathy (DCM). However, the exact pathogenesis remains unclear, resulting in a lack of targeted clinical therapies. The aim of this study is to elucidate the mechanism by which ANXA11 affects DCM by inducing mitochondrial dysfunction through β-hydroxybutyrylation (kbhb).

Methods

Establishing a model through in vivo experiments to detect centrosome amplification, mitochondrial dysfunction, and ANXA11 expression. Co-IP was used to detect the Kbhb modification of ANXA11 and the binding between ANXA11 and Cep55. Western blot and immunofluorescence assay (IF) were used to detect the centrioles duplication related protein γ-Tubulin and polo-like kinase 4 (PLK4). Mitochondrial membrane potential (MMP) and ATP were also assessed.

Results

In vivo and in vitro experiments have shown that centrosome amplification, mitochondrial dysfunction, and significant increase in ANXA11 expression occur in DCM. Co-IP showed that the Kbhb modification of ANXA11 was higher in 30.0 mmol/L glucose treated H9C2 cells and there exist the binding between ANXA11 and Cep55. ANXA11 overexpression increased the expression of γ-Tubulin and PLK4. ANXA11 overexpression also decreased the MMP and ATP level.

Conclusion

These results collectively provide mechanistic insight into the impact of ANXA11 on DCM severity through mitochondrial dysfunction and can be a useful therapeutic approach in patients with DCM.