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Lysine Desuccinylase SIRT5 Binds To Cardiolipin And Regulates The Electron Transport Chain
Yuxun Zhang, Sivakama S. Bharathi, Matthew J Rardin, Jie Lu, Katherine V Maringer, S. Sims-Lucas, E. Prochownik, B. Gibson, E. Goetzman
Published 2017 · Biology, Medicine
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SIRT5 is a lysine desuccinylase known to regulate mitochondrial fatty acid oxidation and the urea cycle. Here, SIRT5 was observed to bind to cardiolipin via an amphipathic helix on its N terminus. In vitro, succinyl-CoA was used to succinylate liver mitochondrial membrane proteins. SIRT5 largely reversed the succinyl-CoA-driven lysine succinylation. Quantitative mass spectrometry of SIRT5-treated membrane proteins pointed to the electron transport chain, particularly Complex I, as being highly targeted for desuccinylation by SIRT5. Correspondingly, SIRT5−/− HEK293 cells showed defects in both Complex I- and Complex II-driven respiration. In mouse liver, SIRT5 expression was observed to localize strictly to the periportal hepatocytes. However, homogenates prepared from whole SIRT5−/− liver did show reduced Complex II-driven respiration. The enzymatic activities of Complex II and ATP synthase were also significantly reduced. Three-dimensional modeling of Complex II suggested that several SIRT5-targeted lysine residues lie at the protein-lipid interface of succinate dehydrogenase subunit B. We postulate that succinylation at these sites may disrupt Complex II subunit-subunit interactions and electron transfer. Lastly, SIRT5−/− mice, like humans with Complex II deficiency, were found to have mild lactic acidosis. Our findings suggest that SIRT5 is targeted to protein complexes on the inner mitochondrial membrane via affinity for cardiolipin to promote respiratory chain function.
This paper references
Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human.
P. Rustin (1997)
Crystal Structure of Mitochondrial Respiratory Membrane Protein Complex II
F. Sun (2005)
The Identification of a Succinyl-CoA Thioesterase Suggests a Novel Pathway for Succinate Production in Peroxisomes*
M. A. K. Westin (2005)
Peroxisomal β-oxidation—A metabolic pathway with multiple functions
Y. Poirier (2006)
High Resolution Clear Native Electrophoresis for In-gel Functional Assays and Fluorescence Studies of Membrane Protein Complexes*
I. Wittig (2007)
Target identification of drug induced mitochondrial toxicity using immunocapture based OXPHOS activity assays.
S. Nadanaciva (2007)
Evidence for Physical Association of Mitochondrial Fatty Acid Oxidation and Oxidative Phosphorylation Complexes
Y. Wang (2010)
Structural and functional characterization of the recombinant human mitochondrial trifunctional protein.
Benjamin Fould (2010)
Direct Interaction of Mitochondrial Targeting Presequences with Purified Components of the TIM23 Protein Complex*
Milit Marom (2011)
Membrane microenvironment regulation of carnitine palmitoyltranferases I and II.
K. Kashfi (2011)
Distinct regulation of mitochondrial localization and stability of two human Sirt5 isoforms
N. Matsushita (2011)
Platform-independent and Label-free Quantitation of Proteomic Data Using MS1 Extracted Ion Chromatograms in Skyline
B. Schilling (2012)
The stability and activity of respiratory Complex II is cardiolipin-dependent.
C. Schwall (2012)
Lipid-binding analysis using a fat blot assay.
T. Munnik (2013)
SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways.
Jeongsoon Park (2013)
Sirtuin 3 (SIRT3) Protein Regulates Long-chain Acyl-CoA Dehydrogenase by Deacetylating Conserved Lysines Near the Active Site
Sivakama S. Bharathi (2013)
Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation.
Brian T. Weinert (2013)
SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks.
Matthew J Rardin (2013)
Widespread and Enzyme-independent Nϵ-Acetylation and Nϵ-Succinylation of Proteins in the Chemical Conditions of the Mitochondrial Matrix*♦
G. R. Wagner (2013)
Cardiolipin-dependent formation of mitochondrial respiratory supercomplexes.
E. Mileykovskaya (2014)
Cardiac Metabolic Pathways Affected in the Mouse Model of Barth Syndrome
Y. Huang (2015)
SIRT3 and SIRT5 Regulate the Enzyme Activity and Cardiolipin Binding of Very Long-Chain Acyl-CoA Dehydrogenase
Yuxun Zhang (2015)
NADP(+)-IDH Mutations Promote Hypersuccinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance.
Feng Li (2015)
MICOS coordinates with respiratory complexes and lipids to establish mitochondrial inner membrane architecture
J. Friedman (2015)
A lacZ reporter gene expression atlas for 313 adult KOMP mutant mouse lines.
David B. West (2015)
Site-Specific Reactivity of Nonenzymatic Lysine Acetylation
J. Baeza (2015)
PGC-1α Promotes Ureagenesis in Mouse Periportal Hepatocytes through SIRT3 and SIRT5 in Response to Glucagon
L. Li (2016)
Abnormal lipid processing but normal long-term repopulation potential of myc−/− hepatocytes
L. Edmunds (2016)
Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function
Sushabhan Sadhukhan (2016)
Cardiac‐specific succinate dehydrogenase deficiency in Barth syndrome
Jan Dudek (2015)
Cardiolipin fatty acid remodeling regulates mitochondrial function by modifying the electron entry point in the respiratory chain.
Aurélia Vergeade (2016)
SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense
L. Zhou (2016)
2nd, and Boutaud, O. (2016) Cardiolipin fatty acid remodeling regulates mitochondrial function by modifying the electron entry point in the respiratory
A. Vergeade (2016)
Aspirin increases mitochondrial fatty acid oxidation.
R. Uppala (2017)
The Reactome pathway knowledgebase
A. Fabregat (2013)
This paper is referenced by
Sirtuins, healthspan, and longevity in mammals
Surinder Kumar (2021)
Sirtuins and cellular metabolism in cancers
Z. Dong (2021)
Post-translational Acetylation Control of Cardiac Energy Metabolism
Ezra B Ketema (2021)
Protein acetylation: a novel modus of obesity regulation.
Yuexia Liu (2021)
Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses
Inseo Choi (2021)
Sirtuins play critical and diverse roles in acute kidney injury
Kevin D Peasley (2021)
Role of succinylation modification in thyroid cancer and breast cancer.
Mitochondrial sirtuins at the crossroads of energy metabolism and oncogenic transformation
M. Grabacka (2021)
Sirtuin 5 levels are limiting in preserving cardiac function and suppressing fibrosis in response to pressure overload
Angela H. Guo (2021)
Sirtuins and next generation hallmarks of cancer: cellular energetics and tumor promoting inflammation
R. Kleszcz (2021)
The deacylase SIRT5 supports melanoma viability by influencing chromatin dynamics.
W. Giblin (2021)
The Role of Epigenetic Changes in the Progression of Alcoholic Steatohepatitis
H. Kim (2021)
Sirtuins, mitochondria, and exercise in health and disease
A. Das (2021)
Phenylalanine hydroxylase deficient phenylketonuria comparative metabolomics identifies energy pathway disruption and oxidative stress.
S. Dobrowolski (2021)
Neuroprotection in Glaucoma: NAD+/NADH Redox State as a Potential Biomarker and Therapeutic Target
Bledi Petriti (2021)
Sirtuin 5 depletion impairs mitochondrial function in human proximal tubular epithelial cells
T. N. Haschler (2021)
The possible role of sirtuin 5 in the pathogenesis of apical periodontitis.
Cheng-Ning Yang (2020)
Citrate synthase desuccinylation by SIRT5 promotes colon cancer cell proliferation and migration
M. Ren (2020)
Impaired mitochondrial medium-chain fatty acid oxidation drives periportal macrovesicular steatosis in sirtuin-5 knockout mice
E. Goetzman (2020)
The NAD+-mitophagy axis in healthy longevity and in artificial intelligence-based clinical applications
Y. Aman (2019)
The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics
W. Giblin (2020)
SIRT5 impairs aggregation and activation of the signaling adaptor MAVS through catalyzing lysine desuccinylation
Xing Liu (2020)
Molecular characterization and expression of sirtuin 2, sirtuin 3, and sirtuin 5 in the Wuchang bream (Megalobrama amblycephala) in response to acute temperature and ammonia nitrogen stress.
Linjie Qian (2020)
Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes
P. Ježek (2019)
Structural insights into the molecular mechanism underlying Sirt5-catalyzed desuccinylation of histone peptides.
T. Hang (2019)
OGDH mediates the inhibition of SIRT5 on cell proliferation and migration of gastric cancer.
Xin Lu (2019)
Succinylation Links Metabolism to Protein Functions
Yun Yang (2019)
An acyl-CoA dehydrogenase microplate activity assay using recombinant porcine electron transfer flavoprotein.
Yuxun Zhang (2019)
The fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase can be a source of mitochondrial hydrogen peroxide
Yuxun Zhang (2019)
SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress
M. Zhang (2019)
Mitochondrial Communication in Physiology, Disease and Aging
Michael R. Duchen (2019)
Regulation of UCP1 and Mitochondrial Metabolism in Brown Adipose Tissue by Reversible Succinylation.
Guoxiao Wang (2019)See more