Hu et al. reveal that SIRT5 confers cuproptosis resistance in LUAD by desuccinylating FDX1 at Lys84 to promote its proteasomal degradation. Combining a SIRT5 inhibitor with a copper ionophore synergistically suppresses LUAD progression, proposing a translatable therapeutic strategy.

Bai et al. demonstrate that AKT1 undergoes lysine glutarylation at the evolutionarily conserved residues K179 and K289. Glutarylation suppresses AKT1 activity by perturbing ATP coordination and PDK1-mediated phosphorylation. This modification is dynamically regulated by the metabolic enzymes GCDH and DHTKD1 and the deglutarylase SIRT5.

Read the full paper: SIRT5-mediated FDX1 desuccinylation confers cuproptosis resistance in lung adenocarcinoma

Read the full paper: AKT1 glutarylation regulated by GCDH and SIRT5 suppresses oncogenic signaling

Staphylococcus aureus (S. aureus)-driven senescence of bovine mammary epithelial cells is a key determinant of mammary gland health, yet its molecular basis remains poorly defined. Sirtuin 5 (SIRT5),...

Mitochondria-derived acyl-coenzyme A (acyl-CoA) species chemically modify proteins, causing damage when acylation reactions are not adequately detoxified by enzymatic removal or protein turnover. Defects in genes encoding the mitochondrial respiratory complex and TCA cycle enzymes have been shown to increase acyl-CoA levels due to reduced enzymatic flux and result in proteome-wide hyperacylation. How pathologically elevated acyl-CoA levels contribute to bioenergetics failure in mitochondrial diseases is not well understood. Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy. To explore this mechanism as a therapeutic target, we developed a workflow to monitor behavioral defects in sucla2–/– zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2–/– zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD+-dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD+ supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.