<i>Drosophila</i> Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity

Rahman, Motiur; Nirala, Niraj K.; Singh, Alka; Zhu, Lihua Julie; Taguchi, Kaori; Bamba, Takeshi; Fukusaki, Eiichiro; Shaw, Leslie M.; Lambright, David G.; Acharya, Jairaj; Acharya, Usha

doi:10.1083/jcb.201404118

Cited by 93 publications

(54 citation statements)

References 67 publications

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“…Various studies have revealed that SIRT3 deacetylates multiple ETC proteins to enhance energy production and improve ETC efficiency, such as NDUFA9 (complex I), SDHA (complex II), and the ATP synthase subunit b (complex V) (1,9,27,40,77,79,125). Moreover, the activities of complexes III and IV are significantly reduced in Sirt3-null mice under high-fat feeding conditions (77).…”

Section: Sirt3 Regulates Multiple Metabolic Pathwaysmentioning

confidence: 99%

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

122

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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.

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Section: Sirt3 Regulates Multiple Metabolic Pathwaysmentioning

confidence: 99%

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

122

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“…SIRT3 physically interacts with and regulates complexes I, II and V within the ETC [4,5,6]. Additionally, SIRT3 has been identified as a regulator of mitochondrial ribosomal protein 10, thus revealing SIRT3's role in the transcriptional modulation of respiratory complexes [8].…”

Section: Sirt3 Regulates Mitochondrial Functionsmentioning

confidence: 99%

“…SIRT3 is a nuclear DNA-encoded, 44 kDa NAD + -dependent deacetylase belonging to the Sirtuin family that comprises 7 proteins in mammals [3]. SIRT3 is localized in the mitochondrial matrix and controls a multitude of processes, including respiratory chain activity, tricarboxylic acid (TCA) cycle, fatty acid β-oxidation, and antioxidant pathway, which are fundamental for the functional integrity of organelles [4,5,6]. In recent years, our understanding of the roles of SIRT3 has extended from the description of a lysine deacetylase to a multifaceted global regulator of mitochondrial adaptive response to stress, indicating a new target for therapy aimed at improving end-organ damage and ultimately survival.…”

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confidence: 99%

Mitochondrial Sirtuin 3 and Renal Diseases

Perico

Morigi

Benigni³

2016

Nephron

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Mitochondria are dynamic organelles whose functions are tightly regulated at multiple levels to maintain proper cellular homeostasis. Mitochondrial Sirtuin 3 (SIRT3), which belongs to an evolutionary conserved family of NAD⁺-dependent deacetylases, is a key regulator of the mitochondrial respiratory chain, ATP production, and fatty acid β-oxidation, and it exerts an antioxidant activity. Changes in SIRT3 expression are critical in the pathophysiology of several diseases, such as metabolic syndrome, diabetes, cancer, and aging. In experimental acute kidney injury (AKI), impairment of renal function and development of tubular injury are associated with SIRT3 reduction and mitochondrial dysfunction in proximal tubuli. SIRT3-deficient mice are more susceptible to AKI and die. Pharmacological manipulations able to increase SIRT3 preserve mitochondrial integrity, markedly limit renal injury, and accelerate functional recovery. This review highlights all the selective rescue mechanisms that point to the key role of SIRT3 as a new therapeutic target for curing renal diseases.

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“…The proteins of the ATP synthase complex undergo numerous posttranslational modifications that can be altered by energy status or oxidative stress; these modifications can affect both the formation and activity of the complex (63)(64)(65)(66). One recent example is the inhibition of ATP synthase by acetylation in the absence of the mitochondrial deacetylase sirtuin 3, which is activated by NAD + (64), showing that alterations in redox status can influence ATP synthase activity.…”

Section: Discussionmentioning

confidence: 99%

Loss of long‐chain acyl‐CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation

et al. 2015

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Because hearts with a temporally induced knockout of acyl-CoA synthetase 1 (Acsl1 T2/2 ) are virtually unable to oxidize fatty acids, glucose use increases 8-fold to compensate. This metabolic switch activates mechanistic target of rapamycin complex 1 (mTORC1), which initiates growth by increasing protein and RNA synthesis and fatty acid metabolism, while decreasing autophagy. Compared with controls, Acsl1 T2/2 hearts contained 3 times more mitochondria with abnormal structure and displayed a 35-43% lower respiratory function. To study the effects of mTORC1 activation on mitochondrial structure and function, mTORC1 was inhibited by treating Acsl1 T2/2 and littermate control mice with rapamycin or vehicle alone for 2 wk. Rapamycin treatment normalized mitochondrial structure, number, and the maximal respiration rate in Acsl1 T2/2 hearts, but did not improve ADP-stimulated oxygen consumption, which was likely caused by the 33-51% lower ATP synthase activity present in both vehicle-and rapamycintreated Acsl1 T2/2 hearts. The turnover of microtubule associated protein light chain 3b in Acsl1 T2/2 hearts was 88% lower than controls, indicating a diminished rate of autophagy. Rapamycin treatment increased autophagy to a rate that was 3.1-fold higher than in controls, allowing the formation of autophagolysosomes and the clearance of damaged mitochondria. Thus, long-chain acyl-CoA synthetase isoform 1 (ACSL1) deficiency in the heart activated mTORC1, thereby inhibiting autophagy and increasing the number of damaged mitochondria.-Grevengoed, T. J., Cooper, D. E., Young, P. A., Ellis, J. M., Coleman, R. A. Loss of long-chain acyl-CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation. FASEB J. 29, 4641-4653 (2015). www.fasebj.orgThe heart alters its substrate use to meet the constant high demand for energy. For example, whereas the heart normally obtains 60-90% of its energy from very LDL-derived fatty acids (1), feeding or hypoxia can increase the use of glucose, whereas fasting can increase the use of amino acids and ketone bodies (2). In diabetes, the impaired uptake of glucose increases the use of fatty acids (3, 4), and conversely, glucose use increases with both heart failure and the pathologic hypertrophy caused by pressure overload (5-8). Because it is unclear whether the switch in substrate use in each of these states is compensatory or pathologic, we asked whether predominant glucose use, in the absence of other cardiac dysfunction, would be detrimental.Acyl-CoA synthetases (ACSLs) convert fatty acids to acylCoAs, which can then be oxidized in the mitochondria to produce energy, incorporated into triacylglycerol (TAG) for storage, or incorporated into phospholipids for membrane biogenesis. Of the 5 long-chain mammalian ACSL isoforms, long-chain acyl-CoA synthetase isoform 1 (ACSL1) is the major isoform in the heart, accounting for 90% of total ACSL activity. In the temporally induced mouse model deficient in ACSL isof...

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Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity

Abstract: Sirtuin-mediated deacetylation of the catalytic subunit of mitochondrial complex V increases complex activity.

Cited by 93 publications

References 67 publications

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Mitochondrial Sirtuin 3 and Renal Diseases

Loss of long‐chain acyl‐CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation

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