SIRT5

SIRT5 is an NAD⁺-dependent mitochondrial sirtuin that functions primarily as a lysine desuccinylase, demalonylase, and deglutarylase rather than a classical deacetylase, thereby regulating post-translational acyl modifications on metabolic proteins^[1][2][3]. Mechanistically, SIRT5 preferentially removes negatively charged acyl groups from lysine residues and controls the activity of numerous enzymes involved in mitochondrial metabolism, including pathways linked to the tricarboxylic acid cycle, fatty acid oxidation, ketogenesis, and the urea cycle^[1][2][4]. Through broad regulation of the mitochondrial succinylome and related acylomes, SIRT5 contributes to cellular energy homeostasis, oxidative metabolism, and redox balance^[4][5][6]. In disease-associated models, altered SIRT5 activity has been linked to cardiac physiology, metabolic disorders, neurodegenerative conditions, and cancer, highlighting its role in metabolic adaptation under physiological and pathological stress^[5][6][7]. Experimental studies further demonstrate that SIRT5 deficiency impairs mitochondrial ATP production, increases the AMP/ATP ratio, and activates AMPK signaling during energy stress, supporting a direct role in mitochondrial bioenergetics^[8]. Compared with related sirtuin isoforms, SIRT5 is distinguished by its strong preference for negatively charged acyl substrates and its relatively weak deacetylase activity, establishing a unique enzymatic profile within the mammalian sirtuin family^[2][3]. For experimental applications, SIRT5 has emerged as a pharmacologically relevant target, and both inhibitors and activity modulators are being investigated to dissect mitochondrial metabolic regulation and disease-associated acylation networks^[9].