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Sirtuin-5 Is Recruited to Hepatic Peroxisomes in Mice Fed Dodecanedioic Acid but Has Little Impact on the Peroxisomal Succinylome.

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Τίτλος: Sirtuin-5 Is Recruited to Hepatic Peroxisomes in Mice Fed Dodecanedioic Acid but Has Little Impact on the Peroxisomal Succinylome.
Συγγραφείς: Zhang Y; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA., Zhang BB; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA., Bharathi SS; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA., Bons J; The Buck Institute for Research on Aging, Novato, CA 94945, USA., Rose JP; The Buck Institute for Research on Aging, Novato, CA 94945, USA., Shah S; The Buck Institute for Research on Aging, Novato, CA 94945, USA., Dobrowolski SF; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Sims-Lucas S; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA., Schilling B; The Buck Institute for Research on Aging, Novato, CA 94945, USA., Goetzman ES; Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA.
Πηγή: Biomolecules [Biomolecules] 2024 Nov 26; Vol. 14 (12). Date of Electronic Publication: 2024 Nov 26.
Τύπος έκδοσης: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101596414 Publication Model: Electronic Cited Medium: Internet ISSN: 2218-273X (Electronic) Linking ISSN: 2218273X NLM ISO Abbreviation: Biomolecules Subsets: MEDLINE
Imprint Name(s): Original Publication: Basel, Switzerland : MDPI, 2011-
Ιατρικοί όροι (MeSH): Peroxisomes*/metabolism , Liver*/metabolism , Sirtuins*/metabolism , Sirtuins*/genetics , Mice, Knockout*, Dicarboxylic Acids/metabolism ; Acyl Coenzyme A/metabolism ; Fatty Acids/metabolism ; Animals ; Mice ; Oxidation-Reduction ; Male ; Mice, Inbred C57BL
Περίληψη: Lysine succinylation, and its reversal by sirtuin-5 (SIRT5), is known to modulate mitochondrial fatty acid β-oxidation (FAO). We recently showed that feeding mice dodecanedioic acid, a 12-carbon dicarboxylic acid (DC12) 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 DC12-induced peroxisomal succinylation, or to regulate peroxisomal FAO in this context, remained unexplored. Here, we showed that feeding DC12 strongly recruits SIRT5 into hepatic peroxisomes. Knocking out SIRT5 impaired peroxisomal FAO as evidenced by reduced 14C-DC12 flux in liver homogenates and elevated levels of partially shortened DC12 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 DC12 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 DC12 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.
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Grant Information: R01 DK134346 United States DK NIDDK NIH HHS; R01 DK121758 United States DK NIDDK NIH HHS; P30 DK120531 United States DK NIDDK NIH HHS; S10 OD028654 United States OD NIH HHS; R01 DK090242 United States DK NIDDK NIH HHS; 1R01DK090242-15A1 United States NH NIH HHS; R01 HD103602 United States HD NICHD NIH HHS; 1R01HD103602-03A1 United States NH NIH HHS
Contributed Indexing: Keywords: fatty acid oxidation; peroxisome; sirtuin-5
Substance Nomenclature: 0 (SIRT5 protein, mouse)
EC 3.5.1.- (Sirtuins)
0 (Dicarboxylic Acids)
0 (Acyl Coenzyme A)
BSI27HW5EQ (succinyl-coenzyme A)
0 (Fatty Acids)
Entry Date(s): Date Created: 20250108 Date Completed: 20250108 Latest Revision: 20260506
Update Code: 20260506
PubMed Central ID: PMC11673421
DOI: 10.3390/biom14121508
PMID: 39766215
Βάση Δεδομένων: MEDLINE
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