{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:37:07Z","timestamp":1788953827046,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T00:00:00Z","timestamp":1652659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172556"],"award-info":[{"award-number":["82172556"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["5214025"],"award-info":[{"award-number":["5214025"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005090","name":"Beijing Municipal Science and Technology Commission","doi-asserted-by":"publisher","award":["82172556"],"award-info":[{"award-number":["82172556"]}],"id":[{"id":"10.13039\/501100005090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005090","name":"Beijing Municipal Science and Technology Commission","doi-asserted-by":"publisher","award":["5214025"],"award-info":[{"award-number":["5214025"]}],"id":[{"id":"10.13039\/501100005090","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>It is known that the activities of nicotine adenine dinucleotide (NAD+)-dependent deacetylase decline in the aging mouse liver, and nicotinamide mononucleotide (NMN)-mediated activation of deacetylase has been shown to increase healthspans. However, age-induced changes of the acetylomic landscape and effects of NMN treatment on protein acetylation have not been reported. Here, we performed immunoprecipitation coupled with label-free quantitative LC-MS\/MS (IPMS) to identify the acetylome and investigate the effects of aging and NMN on liver protein acetylation. In total, 7773 acetylated peptides assigned to 1997 proteins were commonly identified from young and aged livers treated with vehicle or NMN. The major biological processes associated with proteins exhibiting increased acetylation from aged livers were oxidation-reduction and metabolic processes. Proteins with decreased acetylation from aged livers mostly participated in transport and translation processes. Furthermore, NMN treatment inhibited the aging-related increase of acetylation on proteins regulating fatty acid \u03b2 oxidation, the tricarboxylic acid (TCA) cycle and valine degradation. In particular, NAD (P) transhydrogenase (NNT) was markedly hyperacetylated at K70 in aged livers, and NMN treatment decreased acetylation intensity without altering protein levels. Acetylation at cytochrome 3a25 (Cyp3a25) at K141 was also greatly increased in aged livers, and NMN treatment totally arrested this increase. Our extensive identification and analysis provide novel insight and potential targets to combat aging and aging-related functional decline.<\/jats:p>","DOI":"10.3390\/cells11101654","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T13:06:23Z","timestamp":1652706383000},"page":"1654","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Nicotinamide Mononucleotide Administration Amends Protein Acetylome of Aged Mouse Liver"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1738-4031","authenticated-orcid":false,"given":"Chengting","family":"Luo","sequence":"first","affiliation":[{"name":"Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China"},{"name":"MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxi","family":"Ding","sequence":"additional","affiliation":[{"name":"Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China"},{"name":"MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songbiao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China"},{"name":"MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Chen","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7391-5058","authenticated-orcid":false,"given":"Xiaohui","family":"Liu","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9496-1280","authenticated-orcid":false,"given":"Haiteng","family":"Deng","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1042\/bj0870258","article-title":"The presence of acetyl groups in histones","volume":"87","author":"Phillips","year":"1963","journal-title":"Biochem. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1073\/pnas.51.5.786","article-title":"Acetylation and methylation of histones and their possible role in the regulation of rna synthesis","volume":"51","author":"Allfrey","year":"1964","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/268462a0","article-title":"n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells","volume":"268","author":"Riggs","year":"1977","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Waddell, J., Banerjee, A., and Kristian, T. (2021). Acetylation in Mitochondria Dynamics and Neurodegeneration. Cells, 10.","DOI":"10.3390\/cells10113031"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ghosh, A.K. (2021). Acetyltransferase p300 is a Putative Epidrug Target for Amelioration of Cellular Aging-Related Cardiovascular Disease. Cells, 10.","DOI":"10.3390\/cells10112839"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/j.1753-4887.1975.tb05227.x","article-title":"Retarded growth, life span, ultimate body size and age changes in the albino rat after feeding diets restricted in calories","volume":"33","author":"McCay","year":"1975","journal-title":"Nutr. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/35001622","article-title":"Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase","volume":"403","author":"Imai","year":"2000","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1093\/genetics\/116.1.9","article-title":"Four Genes Responsible for a Position Effect on Expression from HML and HMR in Saccharomyces cerevisiae","volume":"116","author":"Rine","year":"1987","journal-title":"Genetics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nrneph.2017.5","article-title":"Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases","volume":"13","author":"Hershberger","year":"2017","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.molcel.2011.12.005","article-title":"The cAMP\/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD(+)","volume":"44","author":"Dominy","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/j.molcel.2013.06.001","article-title":"SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways","volume":"50","author":"Park","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17312","DOI":"10.1074\/jbc.M117.778720","article-title":"Obesity and aging diminish sirtuin 1 (SIRT1)-mediated deacetylation of SIRT3, leading to hyperacetylation and decreased activity and stability of SIRT3","volume":"292","author":"Kwon","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_13","first-page":"6","article-title":"A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis","volume":"105","author":"Kim","year":"2008","journal-title":"PNAS"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1089\/ars.2018.7703","article-title":"Sirt3 Deficiency Shortens Life Span and Impairs Cardiac Mitochondrial Function Rescued by Opa1 Gene Transfer","volume":"31","author":"Benigni","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1007\/s00125-011-2288-0","article-title":"Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function","volume":"54","author":"Caton","year":"2011","journal-title":"Diabetologia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.redox.2018.04.006","article-title":"Nicotinamide riboside attenuates alcohol induced liver injuries via activation of SirT1\/PGC-1alpha\/mitochondrial biosynthesis pathway","volume":"17","author":"Wang","year":"2018","journal-title":"Redox Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.cmet.2012.04.022","article-title":"The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity","volume":"15","author":"Houtkooper","year":"2012","journal-title":"Cell Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.freeradbiomed.2018.05.073","article-title":"Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis","volume":"123","author":"Hong","year":"2018","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.biopen.2015.11.001","article-title":"Identification of a nicotinamide\/nicotinate mononucleotide adenylyltransferase in Giardia lamblia (GlNMNAT)","volume":"1","author":"Buitrago","year":"2015","journal-title":"Biochim. Open"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.cmet.2015.05.023","article-title":"NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus","volume":"22","author":"Canto","year":"2015","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41580-020-00313-x","article-title":"NAD+ metabolism and its roles in cellular processes during ageing","volume":"22","author":"Covarrubias","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_22","first-page":"135","article-title":"Enzymology of NAD+ synthesis","volume":"73","author":"Magni","year":"1999","journal-title":"Adv. Enzymol. Relat. Areas Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.cmet.2016.05.006","article-title":"CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism","volume":"23","author":"Tarrago","year":"2016","journal-title":"Cell Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.cmet.2016.07.005","article-title":"Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle","volume":"24","author":"Frederick","year":"2016","journal-title":"Cell Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1016\/j.neurobiolaging.2012.12.005","article-title":"Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-\u03b3 coactivator 1\u03b1 regulated \u03b2-secretase 1 degradation and mitochondrial gene expression in Alzheimer\u2019s mouse models","volume":"34","author":"Gong","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1016\/j.celrep.2019.07.043","article-title":"Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures","volume":"28","author":"Elhassan","year":"2019","journal-title":"Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.cmet.2016.09.013","article-title":"Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice","volume":"24","author":"Mills","year":"2016","journal-title":"Cell Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.cmet.2011.08.014","article-title":"Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice","volume":"14","author":"Yoshino","year":"2011","journal-title":"Cell Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.freeradbiomed.2020.11.014","article-title":"Nicotinamide mononucleotide inhibits hepatic stellate cell activation to prevent liver fibrosis via promoting PGE2 degradation","volume":"162","author":"Zong","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1016\/j.celrep.2020.01.058","article-title":"NAD+ Repletion Rescues Female Fertility during Reproductive Aging","volume":"30","author":"Bertoldo","year":"2020","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e93885","DOI":"10.1172\/jci.insight.93885","article-title":"Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich\u2019s ataxia cardiomyopathy model","volume":"2","author":"Martin","year":"2017","journal-title":"JCI Insight"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1002\/jnr.24397","article-title":"Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3-dependent mechanism in male mice","volume":"97","author":"Klimova","year":"2019","journal-title":"J. Neurosci. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nature08778","article-title":"SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation","volume":"464","author":"Hirschey","year":"2010","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.molcel.2006.06.026","article-title":"Substrate and functional diversity of lysine acetylation revealed by a proteomics survey","volume":"23","author":"Kim","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14078","DOI":"10.1074\/jbc.M112.355206","article-title":"SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status","volume":"287","author":"Yu","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.molcel.2010.12.013","article-title":"Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress","volume":"40","author":"Tao","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.neuroscience.2014.11.045","article-title":"SIRT3 protects cells from hypoxia via PGC-1alpha- and MnSOD-dependent pathways","volume":"286","author":"Wang","year":"2015","journal-title":"Neuroscience"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10230","DOI":"10.1073\/pnas.0604392103","article-title":"Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases","volume":"103","author":"Hallows","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.exger.2005.06.009","article-title":"Age-related changes in liver structure and function: Implications for disease?","volume":"40","author":"Schmucker","year":"2005","journal-title":"Exp. Gerontol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"108911","DOI":"10.1016\/j.jnutbio.2021.108911","article-title":"Long-term treatment of Nicotinamide mononucleotide improved age-related diminished ovary reserve through enhancing the mitophagy level of granulosa cells in mice","volume":"101","author":"Huang","year":"2022","journal-title":"J. Nutr. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1126\/science.1175371","article-title":"Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions","volume":"325","author":"Choudhary","year":"2009","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.freeradbiomed.2013.05.049","article-title":"A spontaneous mutation in the nicotinamide nucleotide transhydrogenase gene of C57BL\/6J mice results in mitochondrial redox abnormalities","volume":"63","author":"Ronchi","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"101650","DOI":"10.1016\/j.redox.2020.101650","article-title":"Nicotinamide nucleotide transhydrogenase (NNT) regulates mitochondrial ROS and endothelial dysfunction in response to angiotensin II","volume":"36","author":"Rao","year":"2020","journal-title":"Redox Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.freeradbiomed.2019.02.012","article-title":"Estimation of the hydrogen peroxide producing capacities of liver and cardiac mitochondria isolated from C57BL\/6N and C57BL\/6J mice","volume":"135","author":"Oldford","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"16207","DOI":"10.1074\/jbc.RA120.013899","article-title":"Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure","volume":"295","author":"Smith","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"16217","DOI":"10.1074\/jbc.H120.016368","article-title":"The energetic cost of NNT-dependent ROS removal","volume":"295","author":"Kaludercic","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/j.redox.2017.04.035","article-title":"Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation","volume":"12","author":"Ho","year":"2017","journal-title":"Redox Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12967","DOI":"10.1074\/jbc.M112.396796","article-title":"Cofactor balance by nicotinamide nucleotide transhydrogenase (NNT) coordinates reductive carboxylation and glucose catabolism in the tricarboxylic acid (TCA) cycle","volume":"288","author":"Gameiro","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3833","DOI":"10.1016\/j.molcel.2021.06.027","article-title":"Lysine acetylation restricts mutant IDH2 activity to optimize transformation in AML cells","volume":"81","author":"Chen","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3990","DOI":"10.1158\/0008-5472.CAN-16-2393","article-title":"SIRT3-Mediated Dimerization of IDH2 Directs Cancer Cell Metabolism and Tumor Growth","volume":"77","author":"Zou","year":"2017","journal-title":"Cancer Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/10\/1654\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:11:26Z","timestamp":1760137886000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/10\/1654"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,16]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["cells11101654"],"URL":"https:\/\/doi.org\/10.3390\/cells11101654","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,16]]}}}