Letter by Yang et al Regarding Article, “Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2”

HomeCirculationVol. 147, No. 20Letter by Yang et al Regarding Article, “Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Yang et al Regarding Article, “Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2” Yuxue Yang, Daxin Wang and Min Fan Yuxue YangYuxue Yang Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, China (Y.Y., D.W., M.F.). Department of Cardiology, Medical College, Yangzhou University, China (Y.Y.). *Y. Yang and D. Wang contributed equally. Search for more papers by this author , Daxin WangDaxin Wang https://orcid.org/0000-0002-9892-2980 Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, China (Y.Y., D.W., M.F.). *Y. Yang and D. Wang contributed equally. Search for more papers by this author and Min FanMin Fan Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, China (Y.Y., D.W., M.F.). Search for more papers by this author Originally published15 May 2023https://doi.org/10.1161/CIRCULATIONAHA.122.063801Circulation. 2023;147:1560–1561To the Editor:We read with interest the article by Sun et al1 that reported that NR1D1 targets the mitochondrial tricarboxylic acid cycle (TCA) through aconitase-2 (ACO2) transcriptional regulation to influence abdominal aortic aneurysm (AAA) pathogenesis and that α-ketoglutarate (α-KG) supplementation mitigates AAA by restoring mitochondrial metabolism. Mitochondrial metabolites, including intermediates of the TCA, play a role in the pathogenesis of various diseases, and recent studies have revealed that the TCA consists of the classic TCA located in mitochondria and the nonclassic TCA located in the nucleus (nTCA). The classic TCA enzymes, except for succinate dehydrogenase, which is primarily responsible for ATP production, are all present in nTCA; meanwhile, the relevant metabolites such as α-KG, NAD+, acetyl-CoA, and succinyl-CoA are detected in nucleus and involved in the dynamics of DNA/histone modifications.2 The main function of nTCA is not to supply energy but to supply or consume metabolites in the nuclei.2 Pyruvate dehydrogenase, which catalyzes oxidative decarboxylation of pyruvate to produce acetyl-CoA to supply the TCA, is also found in the nucleus, and it was shown that nuclear pyruvate dehydrogenase increases the CoA and metabolite pools in the nuclei, leading to chromatin remodeling of pluripotent genes through enhancement of histone H3 acetylation.3 It is interesting that the immunofluorescence data reported by Sun et al indicated that ACO2 expression, colocalized with the nucleus, was upregulated in NR1D1 knockdown smooth muscle cells after angiotensin II intervention. Therefore, it is presumable that NR1D1 possesses functions other than mitochondrial metabolism regulation; NR1D1 may act as an nTCA enzyme transcription modifier, similar to ACO2 in the nTCA, and may be involved in the histone modifications. Although the amount of ACO2 in nTCA is lower than in TCA located in mitochondria, the molecules in nTCA could interact directly with nucleic substances and possibly have a more profound effect such as epigenetic regulation and phenotype transformation. Supplementation with α-KG, which is a natural product of the human TCA, was shown to postpone AAA progression. In addition, α-KG is one of the key metabolites of the TCA located in mitochondria and nTCA, an important substrate for histone demethylates and an important dioxygenase regulator in the nucleus.4,5 Histone deacetylase 3 is one of the molecules that recruit NR1D1 to the ACO2 promoter region. Therefore, it is conceivable that α-KG mitigates AAA and reverses the detrimental effect of NR1D1 overexpression by inhibiting the binding of NR1D1 to the ACO2 promoter region and affecting the activity of histone demethylates or related enzymes. A deeper understanding of the specific α-KG regulatory mechanisms in AAA pathogenesis is required to broaden the understanding of the multifunctional α-KG and NR1D1 and to facilitate the development of AAA therapeutic strategies. Future studies could evaluate the role of NR1D1 as a transcriptional modulator of nTCA key molecules such as ACO2 and determine the relationship between nTCA and AAA pathogenesis. Such results would provide a deeper understanding of the α-KG effect on histones in AAA, which is important for clinical translation of the study.Article InformationDisclosures None.Footnotes*Y. Yang and D. Wang contributed equally.Circulation is available at www.ahajournals.org/journal/circReferences1. Sun LY, Lyu YY, Zhang HY, Shen Z, Lin GQ, Geng N, Wang YL, Huang L, Feng ZH, Guo X, et al. Nuclear receptor NR1D1 regulates abdominal aortic aneurysm development by targeting the mitochondrial tricarboxylic acid cycle enzyme aconitase-2.Circulation. 2022; 146:1591–1609. doi: 10.1161/CIRCULATIONAHA.121.057623LinkGoogle Scholar2. Liu X, Si W, He L, Yang J, Peng Y, Ren J, Liu X, Jin T, Yu H, Zhang Z, et al. The existence of a nonclassical TCA cycle in the nucleus that wires the metabolic-epigenetic circuitry.Signal Transduct Target Ther. 2021; 6:375. doi: 10.1038/s41392-021-00774-2CrossrefMedlineGoogle Scholar3. Li W, Long Q, Wu H, Zhou Y, Duan L, Yuan H, Ding Y, Huang Y, Wu Y, Huang J, et al. Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation.Nat Commun. 2022; 13:7414. doi: 10.1038/s41467-022-35199-0CrossrefMedlineGoogle Scholar4. Pfau R, Tzatsos A, Kampranis SC, Serebrennikova OB, Bear SE, Tsichlis PN. Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process.Proc Natl Acad Sci U S A. 2008; 105:1907–1912. doi: 10.1073/pnas.0711865105CrossrefMedlineGoogle Scholar5. Rose NR, McDonough MA, King ON, Kawamura A, Schofield CJ. Inhibition of 2-oxoglutarate dependent oxygenases.Chem Soc Rev. 2011; 40:4364–4397. doi: 10.1039/c0cs00203hCrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails May 16, 2023Vol 147, Issue 20 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.063801PMID: 37186681 Originally publishedMay 15, 2023 PDF download Advertisement SubjectsPreeclampsia