IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-36651-5.html
   My bibliography  Save this article

mcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs

Author

Listed:
  • Zhenzhen Chen

    (Zhengzhou University)

  • Qiankun He

    (Zhengzhou University)

  • Tiankun Lu

    (Zhengzhou University)

  • Jiayi Wu

    (Nankai University)

  • Gaoli Shi

    (Zhengzhou University)

  • Luyun He

    (Zhengzhou University)

  • Hong Zong

    (The First Affiliated Hospital of Zhengzhou University)

  • Benyu Liu

    (Zhengzhou University)

  • Pingping Zhu

    (Zhengzhou University)

Abstract

Liver tumour-initiating cells (TICs) contribute to tumour initiation, metastasis, progression and drug resistance. Metabolic reprogramming is a cancer hallmark and plays vital roles in liver tumorigenesis. However, the role of metabolic reprogramming in TICs remains poorly explored. Here, we identify a mitochondria-encoded circular RNA, termed mcPGK1 (mitochondrial circRNA for translocating phosphoglycerate kinase 1), which is highly expressed in liver TICs. mcPGK1 knockdown impairs liver TIC self-renewal, whereas its overexpression drives liver TIC self-renewal. Mechanistically, mcPGK1 regulates metabolic reprogramming by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) and promoting glycolysis. This alters the intracellular levels of α-ketoglutarate and lactate, which are modulators in Wnt/β-catenin activation and liver TIC self-renewal. In addition, mcPGK1 promotes PGK1 mitochondrial import via TOM40 interactions, reprogramming metabolism from oxidative phosphorylation to glycolysis through PGK1-PDK1-PDH axis. Our work suggests that mitochondria-encoded circRNAs represent an additional regulatory layer controlling mitochondrial function, metabolic reprogramming and liver TIC self-renewal.

Suggested Citation

  • Zhenzhen Chen & Qiankun He & Tiankun Lu & Jiayi Wu & Gaoli Shi & Luyun He & Hong Zong & Benyu Liu & Pingping Zhu, 2023. "mcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36651-5
    DOI: 10.1038/s41467-023-36651-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-36651-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-36651-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Sebastian Memczak & Marvin Jens & Antigoni Elefsinioti & Francesca Torti & Janna Krueger & Agnieszka Rybak & Luisa Maier & Sebastian D. Mackowiak & Lea H. Gregersen & Mathias Munschauer & Alexander Lo, 2013. "Circular RNAs are a large class of animal RNAs with regulatory potency," Nature, Nature, vol. 495(7441), pages 333-338, March.
    2. Hao Nie & Haixing Ju & Jiayi Fan & Xiaoliu Shi & Yaxian Cheng & Xiaohui Cang & Zhiguo Zheng & Xiaotao Duan & Wen Yi, 2020. "O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    3. Thomas B. Hansen & Trine I. Jensen & Bettina H. Clausen & Jesper B. Bramsen & Bente Finsen & Christian K. Damgaard & Jørgen Kjems, 2013. "Natural RNA circles function as efficient microRNA sponges," Nature, Nature, vol. 495(7441), pages 384-388, March.
    4. Di Zhang & Zhanyun Tang & He Huang & Guolin Zhou & Chang Cui & Yejing Weng & Wenchao Liu & Sunjoo Kim & Sangkyu Lee & Mathew Perez-Neut & Jun Ding & Daniel Czyz & Rong Hu & Zhen Ye & Maomao He & Y. Ge, 2019. "Metabolic regulation of gene expression by histone lactylation," Nature, Nature, vol. 574(7779), pages 575-580, October.
    5. Bojan Losic & Amanda J. Craig & Carlos Villacorta-Martin & Sebastiao N. Martins-Filho & Nicholas Akers & Xintong Chen & Mehmet E. Ahsen & Johann Felden & Ismail Labgaa & Delia DʹAvola & Kimaada Allett, 2020. "Intratumoral heterogeneity and clonal evolution in liver cancer," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    6. Zhen-zhen Chen & Lan Huang & Ya-hong Wu & Wen-jie Zhai & Ping-ping Zhu & Yan-feng Gao, 2016. "LncSox4 promotes the self-renewal of liver tumour-initiating cells through Stat3-mediated Sox4 expression," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    7. Pingping Zhu & Yanying Wang & Ying Du & Lei He & Guanling Huang & Geng Zhang & Xinlong Yan & Zusen Fan, 2015. "C8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signalling," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    8. Kerstin Hill & Kirstin Model & Michael T. Ryan & Klaus Dietmeier & Falk Martin & Richard Wagner & Nikolaus Pfanner, 1998. "Tom40 forms the hydrophilic channel of the mitochondrial import pore for preproteins," Nature, Nature, vol. 395(6701), pages 516-521, October.
    9. Beverly Y. Mok & Marcos H. de Moraes & Jun Zeng & Dustin E. Bosch & Anna V. Kotrys & Aditya Raguram & FoSheng Hsu & Matthew C. Radey & S. Brook Peterson & Vamsi K. Mootha & Joseph D. Mougous & David R, 2020. "A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing," Nature, Nature, vol. 583(7817), pages 631-637, July.
    10. Pingping Zhu & Yanying Wang & Jiayi Wu & Guanling Huang & Benyu Liu & Buqing Ye & Ying Du & Guangxia Gao & Yong Tian & Lei He & Zusen Fan, 2016. "LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    11. Benyu Liu & Buqing Ye & Xiaoxiao Zhu & Liuliu Yang & Huimu Li & Nian Liu & Pingping Zhu & Tiankun Lu & Luyun He & Yong Tian & Zusen Fan, 2020. "An inducible circular RNA circKcnt2 inhibits ILC3 activation to facilitate colitis resolution," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Bin Li & Wen-Wu Bai & Tao Guo & Zhen-Yu Tang & Xue-Jiao Jing & Ti-Chao Shan & Sen Yin & Ying Li & Fu Wang & Mo-Li Zhu & Jun-Xiu Lu & Yong-Ping Bai & Bo Dong & Peng Li & Shuang-Xi Wang, 2024. "Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Roberta Piras & Emily Y. Ko & Connor Barrett & Marco Simone & Xianzhi Lin & Marina T. Broz & Fernando H. G. Tessaro & Mireia Castillo-Martin & Carlos Cordon-Cardo & Helen S. Goodridge & Dolores Vizio , 2022. "circCsnk1g3- and circAnkib1-regulated interferon responses in sarcoma promote tumorigenesis by shaping the immune microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Yu Dong & Qian Gao & Yong Chen & Zhao Zhang & Yanhua Du & Yuan Liu & Guangxiong Zhang & Shengli Li & Gaoyang Wang & Xiang Chen & Hong Liu & Leng Han & Youqiong Ye, 2023. "Identification of CircRNA signature associated with tumor immune infiltration to predict therapeutic efficacy of immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Ting-Ting He & Yun-Fan Xu & Xiang Li & Xia Wang & Jie-Yu Li & Dan Ou-Yang & Han-Sen Cheng & Hao-Yang Li & Jia Qin & Yu Huang & Hai-Yan Wang, 2023. "A linear and circular dual-conformation noncoding RNA involved in oxidative stress tolerance in Bacillus altitudinis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Mateja Rybiczka-Tešulov & Oxana Garritsen & Morten T. Venø & Laura Wieg & Roland van Dijk & Karim Rahimi & Andreia Gomes-Duarte & Marina de Wit & Lieke L. Haar & Lars Michels & Nicky C. H. van Kronenb, 2024. "Circular RNAs regulate neuron size and migration of midbrain dopamine neurons during development," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    6. Steffen Fuchs & Clara Danßmann & Filippos Klironomos & Annika Winkler & Jörg Fallmann & Louisa-Marie Kruetzfeldt & Annabell Szymansky & Julian Naderi & Stephan H. Bernhart & Laura Grunewald & Konstant, 2023. "Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    7. Xiaojuan Fan & Yun Yang & Chuyun Chen & Zefeng Wang, 2022. "Pervasive translation of circular RNAs driven by short IRES-like elements," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Federica Conte & Giulia Fiscon & Matteo Chiara & Teresa Colombo & Lorenzo Farina & Paola Paci, 2017. "Role of the long non-coding RNA PVT1 in the dysregulation of the ceRNA-ceRNA network in human breast cancer," PLOS ONE, Public Library of Science, vol. 12(2), pages 1-22, February.
    9. Shuangshuang Sun & Zhe Xu & Liying He & Yihui Shen & Yuqing Yan & Xubing Lv & Xujing Zhu & Wei Li & Wei-Ya Tian & Yongjun Zheng & Sen Lin & Yadong Sun & Lei Li, 2024. "Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    10. Lichun Ma & Sophia Heinrich & Limin Wang & Friederike L. Keggenhoff & Subreen Khatib & Marshonna Forgues & Michael Kelly & Stephen M. Hewitt & Areeba Saif & Jonathan M. Hernandez & Donna Mabry & Roman, 2022. "Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    11. Agnieska Brazovskaja & Tomás Gomes & Rene Holtackers & Philipp Wahle & Christiane Körner & Zhisong He & Theresa Schaffer & Julian Connor Eckel & René Hänsel & Malgorzata Santel & Makiko Seimiya & Timm, 2024. "Cell atlas of the regenerating human liver after portal vein embolization," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. Tianshi Feng & Xuemei Zhao & Ping Gu & Wah Yang & Cunchuan Wang & Qingyu Guo & Qiaoyun Long & Qing Liu & Ying Cheng & Jin Li & Cynthia Kwan Yui Cheung & Donghai Wu & Xinyu Kong & Yong Xu & Dewei Ye & , 2022. "Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    13. Marlies Cortés & Agnese Brischetto & M. C. Martinez-Campanario & Chiara Ninfali & Verónica Domínguez & Sara Fernández & Raquel Celis & Anna Esteve-Codina & Juan J. Lozano & Julia Sidorova & Gloria Gar, 2023. "Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Jinchun Wu & Yang Liu & Liqiong Ou & Tingting Gan & Zhengrong Zhangding & Shaopeng Yuan & Xinyi Liu & Mengzhu Liu & Jiasheng Li & Jianhang Yin & Changchang Xin & Ye Tian & Jiazhi Hu, 2024. "Transfer of mitochondrial DNA into the nuclear genome during induced DNA breaks," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    15. Hang Zhou & Wenjun Wang & Hairong Xu & Yong Liang & Jiyu Ding & Mengjie Lv & Boyang Ren & Hua Peng & Yang-Xin Fu & Mingzhao Zhu, 2024. "Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    16. Emily Zhang & Monica E. Neugebauer & Nicholas A. Krasnow & David R. Liu, 2024. "Phage-assisted evolution of highly active cytosine base editors with enhanced selectivity and minimal sequence context preference," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    17. Nana Xu & Jiebang Jiang & Fei Jiang & Guokai Dong & Li Meng & Meng Wang & Jing Chen & Cong Li & Yongping Shi & Sisi He & Rongpeng Li, 2024. "CircCDC42-encoded CDC42-165aa regulates macrophage pyroptosis in Klebsiella pneumoniae infection through Pyrin inflammasome activation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    18. Xiujuan Lei & Wenxiang Zhang, 2019. "BRWSP: Predicting circRNA-Disease Associations Based on Biased Random Walk to Search Paths on a Multiple Heterogeneous Network," Complexity, Hindawi, vol. 2019, pages 1-12, November.
    19. Yue Liu & Yue Yang & Chenying Xu & Jianxing Liu & Jiale Chen & Guoqing Li & Bin Huang & Yi Pan & Yanfeng Zhang & Qiong Wei & Stephen J. Pandol & Fangfang Zhang & Ling Li & Liang Jin, 2023. "Circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    20. Chang Shao & Shuo Tang & Siqin Yu & Chenguang Liu & Yueyang Zhang & Tianyan Wan & Zimeng He & Qi Yuan & Shihan Wu & Hanqing Zhang & Ning Wan & Mengru Zhan & Ren Xiang Tan & Haiping Hao & Hui Ye & Nanx, 2025. "Genetic code expansion reveals site-specific lactylation in living cells reshapes protein functions," Nature Communications, Nature, vol. 16(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36651-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.