Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5
Abstract
The enzymes of the Sirtuin family of nicotinamide-adenine-dinucleotide-dependent protein deacetylases are emerging key players in nuclear and cytosolic signaling, but also in mitochondrial regulation and aging. Mammalian mitochondria contain three Sirtuins, Sirt3, Sirt4, and Sirt5. Only one substrate is known for Sirt3 as well as for Sirt4, and up to now, no target for Sirt5 has been reported. Here, we describe the identification of novel substrates for the human mitochondrial Sirtuin isoforms Sirt3 and Sirt5. We show that Sirt3 can deacetylate and thereby activate a central metabolic regulator in the mitochondrial matrix, glutamate dehydrogenase. Furthermore, Sirt3 deacetylates and activates isocitrate dehydrogenase 2, an enzyme that promotes regeneration of antioxidants and catalyzes a key regulation point of the citric acid cycle. Sirt3 thus can regulate flux and anapleurosis of this central metabolic cycle. We further find that the N- and C-terminal regions of Sirt3 regulate its activity against glutamate dehydrogenase and a peptide substrate, indicating roles for these regions in substrate recognition and Sirtuin regulation. Sirt5, in contrast to Sirt3, deacetylates none of the mitochondrial matrix proteins tested. Instead, it can deacetylate cytochrome c, a protein of the mitochondrial intermembrane space with a central function in oxidative metabolism, as well as apoptosis initiation. Using a mitochondrial import assay, we find that Sirt5 can indeed be translocated into the mitochondrial intermembrane space, but also into the matrix, indicating that localization might contribute to Sirt5 regulation and substrate selection.
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GLUD1 is inhibited by SIRT4 and by acetylation that can be reversed by SIRT3.
“GLUD1 is inhibited by SIRT4 ((Haigis et al. 2006)) and by acetylation which can be reversed by SIRT3 ((Schlicker et al. 2008)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Schlicker et al. 2008
IDH2 function is inhibited by acetylation, and its deacetylation by SIRT3 restores function.
“IDH2 function is inhibited by acetylation, and its deacetylation by SIRT3 restores function ((Schlicker et al. 2008)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Schlicker et al. 2008
SIRT5 removes posttranslational modifications including malonylation, glutarylation, and succinylation on lysine residues.
“SIRT5, a member of the nicotinamide adenine dinucleotide-dependent sirtuin family of protein deacetylases, removes posttranslational modifications including malonylation, glutarylation, and succinylation on lysine residues [204,205].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [204]
Reversible protein acetylation is emerging as a central nutrient-sensing mechanism that integrates metabolic control at multiple levels.
“In addition, reversible protein acetylation is emerging as a central mechanism of nutrient sensing that in turn integrates metabolic control at multiple levels (Hirschey et al., 2009; Schlicker et al., 2008).”
From Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility (2012) · cites this paper as Schlicker et al., 2008
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- Authors
- Schlicker, C., Gertz, M., Papatheodorou, P., Kachholz, B., Becker, C. F. W., & Steegborn, C.
- Affiliations
- Ruhr University Bochum (DE)
- Max Planck Institute of Molecular Physiology (DE)
- Corresponding author
- Steegborn, Clemens
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 382
- Issue
- 3
- Pages
- 790-801
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W2042710774
- Cited by
- 531
- References
- 55
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 17 · 2023: 25 · 2022: 19 · 2021: 36 · 2020: 27 · 2019: 16 · 2018: 32 · 2017: 22 · 2016: 41 · 2015: 25 · 2014: 29 · 2013: 52 · 2012: 42
- FWCI
- 16.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- ERef Bayreuth (University of Bayreuth) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- SIRT3, SIRT5, SIRT4, mitochondrial sirtuins, glutamate dehydrogenase, IDH2, cytochrome c, substrate recognition, mitochondrial matrix, mitochondrial intermembrane space, TCA cycle, mitochondrial protein import, aging, apoptosis
- MeSH terms
- Acetylation, Animals, Enzyme Activation, Fumarate Hydratase, Glutamate Dehydrogenase, Humans, Isocitrate Dehydrogenase, Mitochondria, Models, Molecular, Peptides, Substrate Specificity, Protein Structure, Tertiary, Protein Isoforms, Mitochondrial Proteins, Sirtuins, Cytochromes c, Sirtuin 3
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