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      SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK

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          Abstract

          Efficient coupling of cellular energy production to metabolic demand is crucial to maintain organismal homeostasis. Here, we report that the mitochondrial Sirtuin Sirt4 regulates mitochondrial ATP homeostasis. We find that Sirt4 affects mitochondrial uncoupling via the adenine nucleotide translocator 2 (ANT2). Loss of Sirt4 expression leads to decreased cellular ATP levels in vitro and in vivo while Sirt4 overexpression is associated with increased ATP levels. Further, we provide evidence that lack of Sirt4 activates a retrograde signaling response from the mitochondria to the nucleus that includes AMPK, PGC1α, key regulators of β-oxidation such as Acetyl-CoA carboxylase, and components of the mitochondrial respiratory machinery. This study highlights the ability of Sirt4 to regulate ATP levels via ANT2 and a feedback loop involving AMPK.

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          Mammalian sirtuins: biological insights and disease relevance.

          Marcia Haigis, David A Sinclair (2010)
          Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.
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            SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span.

            Tiara Kawahara, Eriko Michishita, Adam Adler … (2009)
            Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-kappaB signaling. SIRT6 interacts with the NF-kappaB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-kappaB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-kappaB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-kappaB-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-kappaB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-kappaB signaling may contribute to premature and normal aging.
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              The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes.

              R Vega, J Huss, D Kelly (2000)
              Peroxisome proliferator-activated receptor alpha (PPARalpha) plays a key role in the transcriptional control of genes encoding mitochondrial fatty acid beta-oxidation (FAO) enzymes. In this study we sought to determine whether the recently identified PPAR gamma coactivator 1 (PGC-1) is capable of coactivating PPARalpha in the transcriptional control of genes encoding FAO enzymes. Mammalian cell cotransfection experiments demonstrated that PGC-1 enhanced PPARalpha-mediated transcriptional activation of reporter plasmids containing PPARalpha target elements. PGC-1 also enhanced the transactivation activity of a PPARalpha-Gal4 DNA binding domain fusion protein. Retroviral vector-mediated expression studies performed in 3T3-L1 cells demonstrated that PPARalpha and PGC-1 cooperatively induced the expression of PPARalpha target genes and increased cellular palmitate oxidation rates. Glutathione S-transferase "pulldown" studies revealed that in contrast to the previously reported ligand-independent interaction with PPARgamma, PGC-1 binds PPARalpha in a ligand-influenced manner. Protein-protein interaction studies and mammalian cell hybrid experiments demonstrated that the PGC-1-PPARalpha interaction involves an LXXLL domain in PGC-1 and the PPARalpha AF2 region, consistent with the observed ligand influence. Last, the PGC-1 transactivation domain was mapped to within the NH(2)-terminal 120 amino acids of the PGC-1 molecule, a region distinct from the PPARalpha interacting domains. These results identify PGC-1 as a coactivator of PPARalpha in the transcriptional control of mitochondrial FAO capacity, define separable PPARalpha interaction and transactivation domains within the PGC-1 molecule, and demonstrate that certain features of the PPARalpha-PGC-1 interaction are distinct from that of PPARgamma-PGC-1.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Aging (Albany NY)
                Journal ID (iso-abbrev): Aging (Albany NY)
                Journal ID (publisher-id): ImpactJ
                Title: Aging (Albany NY)
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1945-4589
                Publication date Collection: November 2013
                Publication date (Electronic): 26 November 2013
                Volume: 5
                Issue: 11
                Pages: 835-849
                Affiliations
                1 The Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA
                2 Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai, India
                3 The Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
                4 Boston University, Boston, MA 02118, USA
                5 Department of Neurology, University of California, San Francisco, CA 94158, USA
                6 Department of Medicine, University of California, San Francisco, CA 94158, USA
                Author notes
                Correspondence to: Ullas Kolthur-Seetharam, PhD; Eric Verdi, PhD ullas@ 123456tifr.res.in ; eric.verdin@ 123456gladstone.ucsf.edu
                Article
                DOI: 10.18632/aging.100616
                PMC ID: 3868726
                PubMed ID: 24296486
                SO-VID: e51bc888-720d-4ffc-b26a-d573d000d90e
                Copyright © Copyright: © 2013 Ho et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                Date received : 6 November 2013
                Date accepted : 24 November 2013
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Cell biology
                Keywords: sirt4,ant2,ampk,atp,mitochondrial signaling
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: sirt4, ant2, ampk, atp, mitochondrial signaling

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