Sucla2, the ADP-specific beta subunit of succinyl-CoA synthetase (SCS), is crucial in the tricarboxylic acid (TCA) cycle. It catalyzes the conversion of succinyl-CoA to succinate coupled with substrate-level phosphorylation of ADP [2]. This function is essential for energy production and maintaining normal mitochondrial function. Mutations in Sucla2 are associated with mitochondrial encephalomyopathy and mitochondrial DNA maintenance defects [3,4].

In a muscle-specific conditional knock-out (CKO) mouse model of Sucla2, the inactivation led to reduced body weight, muscle weakness, and exercise intolerance. The soleus (SOL) muscle was more severely affected, with decreased specific tetanic force, slower contraction and relaxation rates, increased mitochondria, and changes in the proportion of muscle fiber types [2]. In addition, in ATM (adipose tissue macrophages), siRNA-mediated SUCLA2 knockdown reduced obesity induced by a high-fat diet in mice, indicating its role in the glutaminolysis/AMPK/SUCLA2/IL-1β axis regulating inflammation and obesity [1].

In conclusion, Sucla2 is essential for normal mitochondrial function and energy production through its role in the TCA cycle. The Sucla2 KO/CKO mouse models have revealed its significance in muscle-related mitochondrial myopathy and in the context of obesity-related inflammation. These models provide valuable insights into the disease mechanisms associated with Sucla2 mutations, contributing to a better understanding of the underlying pathologies and potentially guiding future therapeutic strategies.