Succinylation modification: a potential therapeutic target in stroke

Abstract

Stroke is a leading cause of mortality and disability worldwide. Ischemic cell death triggered by the compromised supply of blood oxygen and glucose is one of the major pathophysiology of stroke-induced brain injury. Impaired mitochondrial energy metabolism is observed minutes after stroke and is closely associated with the progression of neuropathology. Recently, a new type of post-translational modification, known as lysine succinylation, has been recognized to play a significant role in mitochondrial energy metabolism after ischemia. However, the role of succinylation modification in cell metabolism after stroke and its regulation are not well understood. We aimed to review the effects of succinylation on energy metabolism, reactive oxygen species generation, and neuroinflammation, as well as Sirtuin 5 mediated desuccinylation after stroke. We also highlight the potential of targeting succinylation/desuccinylation as a promising strategy for the treatment of stroke. The succinylation level is dynamically regulated by the nonenzymatic or enzymatic transfer of a succinyl group to a protein on lysine residues and the removal of succinyl catalyzed by desuccinylases. Mounting evidence has suggested that succinylation can regulate the metabolic pathway through modulating the activity or stability of metabolic enzymes. Sirtuins, especially Sirtuin 5, are characterized for their desuccinylation activity and have been recognized as a critical regulator of metabolism through desuccinylating numerous metabolic enzymes. Imbalance between succinylation and desuccinylation has been implicated in the pathophysiology of stroke. Pharmacological agents that enhance the activity of Sirtuin 5 have been employed to promote desuccinylation and improve mitochondrial metabolism, and neuroprotective effects of these agents have been observed in experimental stroke studies. However, their therapeutic efficacy in stroke patients should be validated.

Keywords: mitochondria metabolism; neuroprotection; sirtuin 5; stroke; succinylation modification.

Figure 1

Regulation of succinylation. The mechanisms of succinylation can be divided into two categories: nonenzymatic modulation and enzymatic modulation. Created with BioRender.com. CPT1A: Palmitoyltransferase 1A; HAT1: histone acetyltransferase 1; KAT2A: lysine acetyltransferase 2A; OGDH: oxoglutarate dehydrogenase; SDH: succinate dehydrogenase; Succ: succinylation; Suc-CoA: succinyl-coenzyme A; SUCLA2: succinyl-CoA synthetase ADP-forming subunit β; α-KGDHC: alpha-ketoglutarate dehydrogenase.

Figure 2

Succinylation affects cell metabolism after stroke, modulates the function of metabolic-related enzymes, and contributes to energy failure and ROS production, resulting in neuronal death and inflammation. Created with BioRender.com. BCAA: Branched-chain amino acid; GLS: glutaminase; IDH2: isocitrate dehydrogenase 2; KGDHC: alpha-ketoglutarate dehydrogenase complex; PDC: pyruvate dehydrogenase complex; SDH: succinate dehydrogenase; Su: succinylation; SUCL: mitochondrial acyl-coenzyme.

Figure 3

Regulation of SIRT5 expression and activity, mediated by substrate, transcriptional regulators, miRNA, and post-transcriptional modification. Created with BioRender.com. BCAA: Branched-chain amino acids; CS: citrate synthase; GLS: glutaminase; IDH2: isocitrate dehydrogenase 2; KGDHC: alpha-ketoglutarate dehydrogenase; PDC: pyruvate dehydrogenase complex; SDH: succinate dehydrogenase; Su: succinylation; Suc-CoA: succinyl-coenzyme A.