SIRT3 deficiency aggravates mitochondrial metabolic disorder and podocyte injury in DKD via MPC2 acetylation

Diabetic kidney disease (DKD) is a chronic disease characterized by high prevalence and mortality rates. Podocyte injury and mitochondrial metabolic disorder are crucial in its progression. Sirtuin3 (SIRT3), a mitochondrial NAD⁺-dependent deacetylase, exerts renoprotective effects in various kidney pathologies by modulating the acetylation status and activity of energy metabolism related substrates. However, its specific roles in podocytes homeostasis during DKD progression remain unclear. We previously reported the role and acetylation level of mitochondrial pyruvate carrier 2 (MPC2) in DKD, but the regulatory mechanism between SIRT3 and MPC2 has not been elucidated. This study aims to investigate the effect of SIRT3 on mitochondrial reprogramming in podocytes and explore the association between SIRT3 and MPC2 during DKD progression.

SIRT3 expression was downregulated in hyperglycemia-induced podocytes in vivo and in vitro. SIRT3 deficiency aggravated podocyte apoptosis and mitochondrial homeostasis dysregulation, as evidenced by increased ROS production, decreased mitochondrial membrane potential and diminished ATP level. However, the overexpression of SIRT3 alleviated these alterations. In addition, we identified a binding interaction between SIRT3 and MPC2. SIRT3 deacetylated MPC2 at lysine K19/K27, mechanistically implicated in the podocyte injury in the process of DKD.

This study validated that hyperglycemia-induced SIRT3-mediated MPC2 acetylation contributes to mitochondrial dysfunction and cellular apoptosis.