Distinct regulation of mitochondrial localization and stability of two human Sirt5 isoforms

Matsushita, Nobuko; Yonashiro, Ryo; Ogata, Yoshinobu; Sugiura, Ayumu; Nagashima, Shun; Fukuda, Toshifumi; Inatome, Ryoko; Yanagi, Shigeru

doi:10.1111/j.1365-2443.2010.01475.x

Cited by 90 publications

(77 citation statements)

References 52 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This amphipathic helix is then removed when the mitochondrial targeting signal is cleaved by the mitochondrial processing peptidase. Interestingly, the mitochondrial processing peptidase cleavage site of SIRT5 leaves an amphipathic helix on the mature protein at the extreme N terminus (12). This N-terminal amphipathic helix has three positively charged residues that orient into the solvent as seen in the SIRT5 crystal structure ( Fig.…”

Section: An N-terminal Amphipathic Helix Mediates Sirt5 Binding To Camentioning

confidence: 99%

Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain

Zhang

Bharathi

Rardin

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by George M. Carman 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. Mitochondrial oxidative energy metabolism is fundamental to human health, and changes in mitochondrial function are now recognized as playing an etiological role in diseases such as cancer, diabetes, and neurodegeneration. Of particular importance to mitochondrial function are the ϳ200 proteins that reside on the inner mitochondrial membrane (IMM).3 IMM proteins include a large family of solute transporters, several ion channels, four electron transport chain (ETC) complexes, and ATP synthase. Additionally, the IMM has many peripherally associated proteins that bind to the membrane electrostatically rather than via transmembrane domains. This group includes enzymes such as carnitine palmitoyltransferase-2, mitochondrial trifunctional protein (MTP), and very-longchain acyl-CoA dehydrogenase (VLCAD), which together catalyze long-chain fatty acid oxidation (FAO). All three show membrane localization through electrostatic binding to cardiolipin on the IMM (1-3). Cardiolipin also appears to facilitate assembly of higher-order ETC "supercomplexes" that mediate maximal respiratory efficiency (4). In an additional layer of complexity, there is increasing evidence that metabolic pathways that directly produce reducing equivalents, such as FAO and the tricarboxylic acid cycle (TCA), can physically interact with the ETC and potentially with each other (5).To date, the factors that regulate metabolic complex assembly and facilitate protein-protein and protein-lipid interactions on the IMM are poorly understood. Reversible post-translational protein modifications such as lysine acylation are widespread in the mitochondria and represent a potential regulatory mechanism for the formation and function of IMM protein complexes. For example, we recently showed that succinylation of three lysine residues in the VLCAD C terminus leads to a complete loss of membrane binding (1). Succinylation converts the positively charged lysine residues to negative charges, thereby disrupting the electrostatic interaction between the amphipathic helix of VLCAD and cardiolipin. Incubation with the mitochondrial desuccinylase SIRT5 restores membrane binding of VLCAD. Mass spectrometry studies have identified SIRT5-targeted lysines on other IMM proteins such as MTP, ADP/ATP translocase, isocitrate dehydrogenase, and hydroxymethylglutaryl-CoA synthase-2 (6 -10), but its role in maintaining the integrity of the IMM proteome has not been directly

show abstract

Section: An N-terminal Amphipathic Helix Mediates Sirt5 Binding To Camentioning

confidence: 99%

Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain

Zhang

Bharathi

Rardin

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…SIRT5 is broadly expressed with the highest expression levels in brain, heart, liver, kidney, muscles, and testis (99,102). SIRT5 is predominantly mitochondrial (33, 99, 102, 137); however, several reports have revealed the existence of functional extra-mitochondrial SIRT5 (46,96,116). In this regard, Park et al reported that a significant amount of SIRT5 is present in the cytosol in mouse hepatocytes and human 293T cells, and that a number of cytosolic and nuclear proteins, in addition to many mitochondrial proteins, were hypersuccinylated in the absence of SIRT5 (116).…”

Section: Sirt5 Regulates Newly Described Ptmsmentioning

confidence: 99%

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

127

View full text Add to dashboard Cite

Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyllysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. Critical Issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context. Future Directions: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease. Antioxid.

show abstract

“…An early study on SIRT5 identified two distinct human isoforms with only minor differences in the C-terminus (54). This study proposed a model where both isoforms of SIRT5 are targeted to the mitochondria for N-terminal processing, which can translocate out of the mitochondria to the cytoplasm and have varying degrees of protein stability (54).…”

mentioning

confidence: 99%

Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation

Hirschey

Zhao

2015

Molecular & Cellular Proteomics

356

311

View full text Add to dashboard Cite

Protein acetylation is a well-studied regulatory mechanism for several cellular processes, ranging from gene expression to metabolism. Recent discoveries of new post-translational modifications, including malonylation, succinylation, and glutarylation, have expanded our understanding of the types of modifications found on proteins. These three acidic lysine modifications are structurally similar but have the potential to regulate different proteins in different pathways. The deacylase sirtuin 5 (SIRT5) catalyzes the removal of these modifications from a wide range of proteins in different subcellular compartments. Here, we review these new modifications, their regulation by SIRT5, and their emerging role in cellular regulation and diseases. Molecular & Cellular

show abstract

Distinct regulation of mitochondrial localization and stability of two human Sirt5 isoforms

Cited by 90 publications

References 52 publications

Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain

Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation

Contact Info

Product

Resources

About