Volume 24 Issue 6
Jun.  2026
Turn off MathJax
Article Contents
Article Navigation >  Chinese Journal of General Practice  > 2026  >  24(6): 1010-1013
RUAN Hejing, ZHAO Wen, LI Dongdong, ZHAO Jiufa. Exploring the mechanisms of mitochondrial and endoplasmic reticulum dysfunction in metabolic associated fatty liver disease[J]. Chinese Journal of General Practice, 2026, 24(6): 1010-1013. doi: 10.16766/j.cnki.issn.1674-4152.004542
Citation: RUAN Hejing, ZHAO Wen, LI Dongdong, ZHAO Jiufa. Exploring the mechanisms of mitochondrial and endoplasmic reticulum dysfunction in metabolic associated fatty liver disease[J]. Chinese Journal of General Practice, 2026, 24(6): 1010-1013. doi: 10.16766/j.cnki.issn.1674-4152.004542
shu

Exploring the mechanisms of mitochondrial and endoplasmic reticulum dysfunction in metabolic associated fatty liver disease

doi: 10.16766/j.cnki.issn.1674-4152.004542

  • Department of Infectious Diseases, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China

Funds:

 82570714

  • Received Date: 2025-09-16
    Available Online: 2026-11-10
    Abstract
  •   Objective  Metabolic associated fatty liver disease (MAFLD) is a chronic liver condition pathologically defined by insulin resistance and excessive hepatic lipid accumulation. Despite its escalating global health burden, no targeted therapy is yet available. This review systematically delineates the roles of three interconnected pathological hubs: (1) Mitochondrial dysfunction, featuring impaired fatty acid oxidation, ROS overproduction, aberrant dynamics, and defective autophagy, which collectively precipitate an energy crisis and lipotoxicity; (2) Endoplasmic reticulum stress (ERS) drives a dynamic shift from compensatory protection to pathological injury during disease progression through the three unfolded protein response (UPR) signaling pathways-IRE1α, PERK, and ATF6. The precise regulation of this signaling dynamics has thus emerged as a key target for therapeutic intervention; (3) Structural and functional alterations in mitochondria-associated endoplasmic reticulum membranes (MAMs)-a central hub for inter-organelle communication-lead to calcium homeostasis imbalance, lipid metabolism disorders, and impaired insulin signaling, thereby integrating and amplifying upstream stress signals to drive disease progression toward hepatitis and fibrosis. By synthesizing the crosstalk within this network, this review aims to identify novel targets for MAFLD intervention.

     

    • FullText(HTML)
  • loading
    • References(42)
  • [1]
    ESLAM M, SANYAL A J, GEORGE J, et al. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease[J]. Gastroenterology, 2020, 158(7): 1999-2014. e1. doi: 10.1053/j.gastro.2019.11.312
    [2]
    MARTÍN-FERNÁNDEZ M, ARROYO V, CARNICERO C, et al. Role of oxidative stress and lipid peroxidation in the pathophysiology of NAFLD[J]. Antioxidants, 2022, 11(11): 2217. DOI: 10.3390/antiox11112217.
    [3]
    中华医学会肝病学分会. 代谢相关(非酒精性)脂肪性肝病防治指南(2024年版)[J]. 中华肝脏病杂志, 2024, 32(5): 418-434.

    Chinese Medical Association Hepatology Branch. Guidelines for the prevention and treatment of metabolic dysfunction-associated (non-alcoholic) fatty liver disease (version 2024)[J]. Chinese Journal of Hepatology, 2024, 32(5): 418-434.
    [4]
    TENG M L, NG C H, HUANG D Q, et al. Global incidence and prevalence of nonalcoholic fatty liver disease[J]. Clin Mol Hepatol, 2023, 29(Suppl): S32-S42. doi: 10.3350/cmh.2022.0365
    [5]
    吴欢, 伍龙, 张宝芳. 线粒体-炎症小体通路在慢性肝脏疾病中的作用[J]. 中华全科医学, 2025, 23(4): 651-655. doi: 10.16766/j.cnki.issn.1674-4152.003972

    Wu H, Wu L, Zhang B F. The role of the mitochondria-inflammasome pathway in the progression of chronic liver disease[J]. Chinese Journal of General Practice, 2025, 23(4): 651-655. doi: 10.16766/j.cnki.issn.1674-4152.003972
    [6]
    GRAYSON C, FAERMAN B, KOUFOS O, et al. Fatty acid oxidation drives mitochondrial hydrogen peroxide production by α-ketoglutarate dehydrogenase[J]. J Biol Chem, 2024, 300(4): 107159. DOI: 10.1016/j.jbc.2024.107159.
    [7]
    YI H S. The role of carnitine orotate complex in fatty liver[J]. Diabetes Metab J, 2021, 45(6): 866-867. doi: 10.4093/dmj.2021.0272
    [8]
    DU D, LIU C, QIN M, et al. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma[J]. Acta Pharm Sin B, 2022, 12(2): 558-580. doi: 10.1016/j.apsb.2021.09.019
    [9]
    WANG C H, WEI Y H. Roles of mitochondrial sirtuins in mitochondrial function, redox homeostasis, insulin resistance and type 2 diabetes[J]. Int J Mol Sci, 2020, 21(15): 5266. DOI: 10.3390/ijms21155266.
    [10]
    YANG S, WANG X, ZHANG Y, et al. SIRT3 regulates CPT1a acetylation and fatty acid oxidation in renal tubular epithelial cells under diabetic condition[J]. Mol Biol Rep, 2025, 52(1): 603. DOI: 10.1007/s11033-025-10712-y.
    [11]
    ABDELLATIF M, VASQUES-NÓVOA F, FERREIRA J P, et al. NAD+ repletion restores cardioprotective autophagy and mitophagy in obesity-associated heart failure by suppressing excessive trophic signaling[J]. Autophagy, 2025, 21(10): 2296-2298. doi: 10.1080/15548627.2025.2522127
    [12]
    QIAO L, LIN X, LIU H, et al. T-2 toxin induces cardiac fibrosis by causing metabolic disorders and up-regulating Sirt3/FoxO3α/MnSOD signaling pathway-mediated oxidative stress[J]. J Environ Sci, 2025, 150: 532-544. doi: 10.1016/j.jes.2024.03.001
    [13]
    SONG Y F, ZHENG H, LUO Z, et al. Dietary choline alleviates high-fat diet-induced hepatic lipid dysregulation via UPRmt modulated by SIRT3-mediated mtHSP70 deacetylation[J]. Int J Mol Sci, 2022, 23(8): 4204. DOI: 10.3390/ijms23084204.
    [14]
    YOVAL-SÁNCHEZ B, GUERRERO I, ANSARI F, et al. Effect of alternative oxidase (AOX) expression on mouse cerebral mitochondria bioenergetics[J]. Redox Biol, 2024, 77: 103378. DOI: 10.1016/j.redox.2024.103378.
    [15]
    CHIANG C H, HSU P S, LIN S P, et al. High-fat diet restriction to adult male mice maintains normal body weight but leads to liver impairment by disrupting mitochondrial oxidative phosphorylation[J]. J Nutr Biochem, 2025, 143: 109941. DOI: 10.1016/j.jnutbio.2025.109941.
    [16]
    YU M, ALIMUJIANG M, HU L, et al. Berberine alleviates lipid metabolism disorders via inhibition of mitochondrial complex Ⅰ in gut and liver[J]. Int J Biol Sci, 2021, 17(7): 1693-1707. doi: 10.7150/ijbs.54604
    [17]
    呼欣怡, 沈佳妍, 应天昊, 等. 线粒体动力学调控在脂肪性肝病中的作用及机制研究进展[J]. 药学学报, 2025, 60(8): 2405-2416.

    Hu X Y, Shen J Y, Ying T X, et al. Research progress on the role and mechanism of mitochondrial dynamics regulation in steatotic liver disease[J]. Acta Pharmaceutica Sinica, 2025, 60(8): 2405-2416.
    [18]
    WANG J, QIU Y, YANG L, et al. Preserving mitochondrial homeostasis protects against drug-induced liver injury via inducing OPTN (optineurin)-dependent mitophagy[J]. Autophagy, 2024, 20(12): 2677-2696. doi: 10.1080/15548627.2024.2384348
    [19]
    ARCONZO M, PICCININ E, PASCULLI E, et al. Hepatic-specific pgc-1α ablation drives fibrosis in a MASH model[J]. Liver Int, 2024, 44(10): 2738-2752. doi: 10.1111/liv.16052
    [20]
    PANG J, YIN L, JIANG W, et al. Sirt1-mediated deacetylation of PGC-1α alleviated hepatic steatosis in type 2 diabetes mellitus via improving mitochondrial fatty acid oxidation[J]. Cell Signal, 2024, 124: 111478. DOI: 10.1016/j.cellsig.2024.111478.
    [21]
    ZENG W, WANG L, WANG C, et al. SENP1 prevents high fat diet-induced non-alcoholic fatty liver diseases by regulating mitochondrial dynamics[J]. Biochim Biophys Acta Mol Basis Dis, 2025, 1871(1): 167527. DOI: 10.1016/j.bbadis.2024.167527.
    [22]
    MAKINWA Y, LUO Y, MUSICH P R, et al. Canonical and noncanonical functions of the BH3 domain protein bid in apoptosis, oncogenesis, cancer therapeutics, and aging[J]. Cancers, 2024, 16(12): 2199. DOI: 10.3390/cancers16122199.
    [23]
    赵淑杰, 方伟伦, 韦瑜, 等. AMPKα2调控IRE1α-JNK通路介导代谢功能障碍相关脂肪性肝病的作用[J]. 中南大学学报医学版, 2024, 49(12): 1891-1901.
    [24]
    WANG J, LI Q, HUO Y, et al. ASPP2 deficiency promotes the progression of metabolic dysfunction-associated steatohepatitis via ACSL4 upregulation[J]. Sci Rep, 2024, 14(1): 29177. DOI: 10.1038/s41598-024-80415-0.
    [25]
    AJOOLABADY A, KAPLOWITZ N, LEBEAUPIN C, et al. Endoplasmic reticulum stress in liver diseases[J]. Hepatology, 2022, 77(2): 619-639.
    [26]
    ZHENG L, LI B, YUAN A, et al. TFEB activator tanshinone ⅡA and derivatives derived from salvia miltiorrhiza bge. Attenuate hepatic steatosis and insulin resistance[J]. J Ethnopharmacol, 2024, 335: 118662. DOI: 10.1016/j.jep.2024.118662.
    [27]
    DASGUPTA D, NAKAO Y, MAUER A S, et al. IRE1A stimulates hepatocyte-derived extracellular vesicles that promote inflammation in mice with steatohepatitis[J]. Gastroenterology, 2020, 159(4): 1487-1503. e17. doi: 10.1053/j.gastro.2020.06.031
    [28]
    JIN S, YAN M, LIU Y, et al. RETREG1-mediated reticulophagy is activated by an ATF4-CEBPG/C/EBPγ heterodimer and confers protection against lipotoxicity[J]. Autophagy, 2025, 21(12): 2614-2632. doi: 10.1080/15548627.2025.2512884
    [29]
    GUO Q, XIN M, LU Q, et al. A novel NEDD4L-TXNIP-CHOP axis in the pathogenesis of nonalcoholic steatohepatitis[J]. Theranostics, 2023, 13(7): 2210-2225. doi: 10.7150/thno.81192
    [30]
    LI J, HUANG L, XIONG W, et al. Effect of aerobic exercise on GRP78 and ATF6 expressions in mice with non-alcoholic fatty liver disease[J]. Sports Med Health Sci, 2023, 5(2): 112-119. doi: 10.1016/j.smhs.2022.11.002
    [31]
    LIU C, ZHOU B, MENG M, et al. FOXA3 induction under endoplasmic reticulum stress contributes to non-alcoholic fatty liver disease[J]. J Hepatol, 2021, 75(1): 150-162. doi: 10.1016/j.jhep.2021.01.042
    [32]
    ZHAO Q, LIU J, DENG H, et al. Targeting mitochondria-located circRNA SCAR alleviates NASH via reducing mROS output[J]. Cell, 2020, 183(1): 76-93. e22. doi: 10.1016/j.cell.2020.08.009
    [33]
    XIAO M C, JIANG N, CHEN L L, et al. TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability[J]. J Hepatol, 2024, 80(5): 778-791. doi: 10.1016/j.jhep.2023.12.029
    [34]
    BEAULANT A, DIA M, PILLOT B, et al. Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis[J]. J Hepatol, 2022, 77(3): 710-722. doi: 10.1016/j.jhep.2022.03.017
    [35]
    XIAN T, LIU Y, YE Y, et al. Human salivary histatin 1 regulating IP3R1/GRP75/VDAC1 mediated mitochondrial-associated endoplasmic reticulum membranes (MAMs) inhibits cell senescence for diabetic wound repair[J]. Free Radic Biol Med, 2024, 225: 164-180. doi: 10.1016/j.freeradbiomed.2024.09.046
    [36]
    MOHAN S, NAIR A, POORNIMA M S, et al. Vanillic acid mitigates hyperinsulinemia induced ER stress mediated altered calcium homeostasis, MAMs distortion and surplus lipogenesis in HepG2 cells[J]. Chem Biol Interact, 2023, 375: 110365. DOI: 10.1016/j.cbi.2023.110365.
    [37]
    BASSOT A, PRIP-BUUS C, ALVES A, et al. Loss and gain of function of Grp75 or mitofusin 2 distinctly alter cholesterol metabolism, but all promote triglyceride accumulation in hepatocytes[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2021, 1866(12): 159030. DOI: 10.1016/j.bbalip.2021.159030.
    [38]
    CHI Y J, BAI Z Y, FENG G L, et al. ER-mitochondria contact sites regulate hepatic lipogenesis via Ip3r-Grp75-vdac complex recruiting seipin[J]. CCS, 2024, 22(1): 464. DOI: 10.1186/s12964-024-01829-x.
    [39]
    NANDWANI A, RATHORE S, DATTA M. LncRNA H19 inhibition impairs endoplasmic reticulum-mitochondria contact in hepatic cells and augments gluconeogenesis by increasing VDAC1 levels[J]. Redox Biol, 2024, 69: 102989. DOI: 10.1016/j.redox.2023.102989.
    [40]
    ZHANG C, SUN X, WU D, et al. IP3R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage[J]. Theriogenology, 2024, 229: 147-157. doi: 10.1016/j.theriogenology.2024.08.023
    [41]
    YANG M, LI C, SUN L. Mitochondria-associated membranes (MAMs): a novel therapeutic target for treating metabolic syndrome[J]. Curr Med Chem, 2021, 28(7): 1347-1362. doi: 10.2174/0929867327666200212100644
    [42]
    LI Y, TIAN X, YU Q, et al. Alleviation of hepatic insulin resistance and steatosis with NMN via improving endoplasmic reticulum-mitochondria miscommunication in the liver of HFD mice[J]. Biomed Pharmacother, 2024, 175: 116682. DOI: 10.1016/j.biopha.2024.116682.
    • Relative Articles
    • Supplements(0)
    • Cited By

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索
    Get Citation
    PDF
    XML

    Article Metrics

    Article views (12) PDF downloads(1) Cited by()
    Proportional views
    Related

    Address：No. 287, Changhuai Road, Bengbu, Anhui Province, 233004, P.R.ChinaphoneNo：0552-3066635； 0552-3051890Email：zhqkyx@163.com

    Copyright © Chinese Journal of General Practice皖ICP备2020018345号-2

    Supported by: Beijing Renhe Information Technology Co., Ltd.    

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return