| First Author | Zhang Y | Year | 2024 |
| Journal | Biomolecules | Volume | 14 |
| Issue | 12 | PubMed ID | 39766215 |
| Mgi Jnum | J:361337 | Mgi Id | MGI:7850958 |
| Doi | 10.3390/biom14121508 | Citation | Zhang Y, et al. (2024) Sirtuin-5 Is Recruited to Hepatic Peroxisomes in Mice Fed Dodecanedioic Acid but Has Little Impact on the Peroxisomal Succinylome. Biomolecules 14(12) |
| abstractText | Lysine succinylation, and its reversal by sirtuin-5 (SIRT5), is known to modulate mitochondrial fatty acid beta-oxidation (FAO). We recently showed that feeding mice dodecanedioic acid, a 12-carbon dicarboxylic acid (DC(12)) that can be chain-shortened four rounds to succinyl-CoA, drives high-level protein hypersuccinylation in the peroxisome, particularly on peroxisomal FAO enzymes. However, the ability of SIRT5 to reverse DC(12)-induced peroxisomal succinylation, or to regulate peroxisomal FAO in this context, remained unexplored. Here, we showed that feeding DC(12) strongly recruits SIRT5 into hepatic peroxisomes. Knocking out SIRT5 impaired peroxisomal FAO as evidenced by reduced (14)C-DC(12) flux in liver homogenates and elevated levels of partially shortened DC(12) catabolites in urine. Further, mass spectrometry revealed a trend toward less peroxisomal protein succinylation in SIRT5 knockout liver. This is consistent with a reduced flux of DC(12) through the peroxisomal FAO pathway, thereby reducing the production of the succinyl-CoA that chemically reacts with lysine residues to produce protein succinylation. Mass spectrometry comparisons of site-level succinylation in wildtype and SIRT5 knockout liver did not reveal any clear pattern of SIRT5 target sites in the peroxisome after DC(12) feeding. However, SIRT5 co-immunoprecipitated with 15 peroxisomal proteins, including the key peroxisomal FAO enzymes acyl-CoA oxidase-1 and enoyl-CoA/3-hydroxyacyl-CoA dehydrogenase (EHHADH). In vitro, recombinant SIRT5 partially desuccinylated chemically modified recombinants ACOX1a, ACOX1b, and EHHADH. Desuccinylation by SIRT5 had no effect on enzyme activity for ACOX1a and EHHADH. For ACOX1b, SIRT5-mediated desuccinylation decreased activity by ~15%. Possible interpretations of these data are discussed. |
