SUCLA2 Inhibited Lysine Succinylation of SHMT2 to Suppress Ferroptosis and Renal Interstitial Fibrosis

Renal interstitial fibrosis (RIF) is a common pathway to end-stage renal diseases progressing towards renal failure. Angiotensin II (Ang II), as the core effector molecule of the renin-angiotensin system (RAS), is widely recognized as a key factor promoting RIF. Succinyl-CoA ligase subunit-beta (SUCLA2) can reversibly convert succinyl CoA into succinate and participates in many biological processes. This research was designed to explore the roles and mechanisms of SUCLA2 in RIF. Ang II-induced mouse model and HK-2 cell model were established. Ang II induced significant histological damage and interstitial fibrosis in mouse kidneys. SUCLA2 mRNA and protein levels were decreased, but lysine succinylation levels were increased in renal tissues of Ang II-induced mice and Ang II-treated HK-2 cells. Overexpression of SUCLA2 inhibited Ang II-induced ferroptosis, along with decreased lysine succinylation and succinyl-CoA levels. SUCLA2 negatively regulated lysine succinylation of SHMT2. Furthermore, SHMT2 desuccinylation by sirtuin 5 (SIRT5) inhibited Ang II-induced ferroptosis, and the inhibitory effect of SUCLA2 overexpression on Ang II-induced ferroptosis was restored by SHMT2 silencing. In vivo, the delivery of adeno-associated virus-mediated SUCLA2-expressing vector into mouse kidneys alleviated Ang II-induced histological damage and interstitial fibrosis. Our research has revealed SUCLA2 inhibited lysine succinylation of SHMT2 to repress renal cell ferroptosis and interstitial fibrosis.