Hezhi Fang

Wenzhou Medical University

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Jianxin Lyu

Wenzhou Medical University

Lijun Shen

Wenzhou Medical University

Qiongya Zhao

Zhejiang Provincial People's Hospital

Yidong Bai

The University of Texas Health Science Center at San Antonio

Huaibin Zhou

Wenzhou Medical University

Yanling Yang

Shanxi Academy of Medical Sciences

Xiujuan Wei

Sichuan Mianyang 404 Hospital

Miaomiao Du

Hangzhou Medical College

Jianxin Lü

Wenzhou Medical University

Ya Wang

Wenzhou Medical University

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Wenzhou Medical University

165

Capital Medical University

Peking University

Shanghai Jiao Tong University

Chinese Academy of Sciences

Central South University

Beijing Children’s Hospital

Chinese Academy of Medical Sciences & Peking Union Medical College

Sichuan University

Sun Yat-sen University

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The mitochondrial DNA 4,977-bp deletion and its implication in copy number alteration in colorectal cancer

BMC Medical Genetics (2011)

Tao Chen Jing He Lijun Shen Hezhi Fang Hezhongrong Nie

Abstract Background Qualitative and quantitative changes in human mitochondrial DNA (mtDNA) have been implicated in various cancer types. A 4,977 bp deletion in the major arch of the mitochondrial genome is one of the most common mutations associated with a variety of human diseases and aging. Methods We conducted a comprehensive study on clinical features and mtDNA of 104 colorectal cancer patients in the Wenzhou area of China. In particular, using a quantitative real time PCR method, we analyzed the 4,977 bp deletion and mtDNA content in tumor tissues and paired non-tumor areas from these patients. Results We found that the 4,977 bp deletion was more likely to be present in patients of younger age (≤65 years, p = 0.027). In patients with the 4,977 bp deletion, the deletion level decreased as the cancer stage advanced (p = 0.031). Moreover, mtDNA copy number in tumor tissues of patients with this deletion increased, both compared with that in adjacent non-tumor tissues and with in tumors of patients without the deletion. Such mtDNA content increase correlated with the levels of the 4,977 bp deletion and with cancer stage (p < 0.001). Conclusions Our study indicates that the mtDNA 4,977 bp deletion may play a role in the early stage of colorectal cancer, and it is also implicated in alteration of mtDNA content in cancer cells.

Human genetics

10.1186/1471-2350-12-8

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Citations (116)

GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity

Diabetes (2021)

Qiongya Zhao Ting Luo Feng Gao Yinxu Fu Bin Li

GRP75 (75-kDA glucose-regulated protein), defined as a major component of both the mitochondrial quality control system and mitochondria-associated membrane, plays a key role in mitochondrial homeostasis. In this study, we assessed the roles of GRP75, other than as a component, in insulin action in both in vitro and in vivo models with insulin resistance. We found that GRP75 was downregulated in mice fed a high-fat diet (HFD) and that induction of Grp75 in mice could prevent HFD-induced obesity and insulin resistance. Mechanistically, GRP75 influenced insulin sensitivity by regulating mitochondrial function through its modulation of mitochondrial-supercomplex turnover rather than mitochondria-associated membrane communication: GRP75 was negatively associated with respiratory chain complex activity and was essential for mitochondrial-supercomplex assembly and stabilization. Moreover, mitochondrial dysfunction in Grp75-knockdown cells might further increase mitochondrial fragmentation, thus triggering cytosolic mtDNA release and activating the cGAS/STING-dependent proinflammatory response. Therefore, GRP75 can serve as a potential therapeutic target of insulin resistant-related diabetes or other metabolic diseases.

10.2337/db21-0173

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HPDL deficiency causes a neuromuscular disease by impairing the mitochondrial respiration

Journal of genetics and genomics/Journal of Genetics and Genomics (2021)

Yu Sun Xiujuan Wei Fang Fang Yiping Shen Haiyan Wei

Mitochondrial disease

10.1016/j.jgg.2021.01.009

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Citations (10)

A Novel NDUFS3 mutation in a Chinese patient with severe Leigh syndrome

Journal of Human Genetics (2018)

Xiaoting Lou Hao Shi Shumeng Wen Yuanyuan Li Xiujuan Wei

Leigh disease

10.1038/s10038-018-0505-0

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Comparative analysis and optimization of protocols for producing recombinant lentivirus carrying the anti‐Her2 chimeric antigen receptor gene

The Journal of Gene Medicine (2018)

Weihua Yuan Jie Chen Ying Cao Lingcong Yang Luxi Shen

The production of anti-Her2 chimeric antigen receptor (CAR) T cells needs to be optimized to make it a reliable therapy.Three types of lentiviral vectors expressing anti-Her2 CAR together with packaging plasmids were co-transfected into 293 T-17 cells. The vector with the best packaging efficiency was selected, and the packaging cell culture system and packaging plasmid system were optimized. Centrifugation speed was optimized for the concentration of lentivirus stock. The various purification methods used included membrane filtration, centrifugation with a sucrose cushion and the novelly-designed instantaneous high-speed centrifugation. The recombinant lentiviruses were transduced into human peripheral T cells with an optimized multiplicity of infection (MOI). CAR expression levels by three vectors and the efficacy of CAR-T cells were compared.When co-transfected, packaging cells in suspension were better than the commonly used adherent culture condition, with the packaging system psPAX2/pMD2.G being better than pCMV-dR8.91/pVSV-G. The optimal centrifugation speed for concentration was 20 000 g, rather than the generally used ultra-speed. Importantly, adding instantaneous centrifugation for purification significantly increased human peripheral T cell viability (from 13.25% to 62.80%), which is a technical breakthrough for CAR-T cell preparation. The best MOI value for transducing human peripheral T cells was 40. pLVX-EF1a-CAR-IRES-ZsGreen1 expressed the highest level of CAR in human peripheral T cells and the cytotoxicity of CAR-T cells reached 63.56%.We optimized the preparation of recombinant lentivirus that can express third-generation anti-Her2 CAR in T cells, which should lay the foundation for improving the efficacy of CAR-T cells with respect to killing target cells.

Multiplicity of infection

Differential centrifugation

10.1002/jgm.3027

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Exercise intolerance and developmental delay associated with a novel mitochondrial ND5 mutation

Scientific Reports (2015)

Hezhi Fang Hao Shi Xiyuan Li Dayan Sun Fengjie Li

The aim of this study was to evaluate the contribution of mitochondrial DNA (mtDNA) mutations in oxidative phosphorylation (OXPHOS) deficiency. The complete mitochondrial genomes of 41 families with OXPHOS deficiency were screened for mutations. Mitochondrial functional analysis was then performed in primary and cybrid cells containing candidate mutations identified during the screening. A novel mitochondrial NADH dehydrogenase 5 (ND5) m.12955A > G mutation was identified in a patient with exercise intolerance and developmental delay. A biochemical analysis revealed deficiencies in the activity of complex I (NADH:quinone oxidoreductase) and IV (cytochrome c oxidase) of this patient. Defects in complexes I and IV were confirmed in transmitochondrial cybrid cells containing the m.12955A > G mutation, suggesting that this mutation impairs complex I assembly, resulting in reduced stability of complex IV. Further functional investigations revealed that mitochondria with the m.12955A > G mutation exhibited lower OXPHOS coupling respiration and adenosine triphosphate (ATP) generation. In addition, the cytotoxic effects, determined as reactive oxygen species (ROS) and lactate levels in the present study, increased in the cells carrying a higher m.12955A > G mutant load. In conclusion, we identified m.12955A > G as a mitochondrial disease-related mutation. Therefore, screening of m.12955A > G is advised for the diagnosis of patients with mitochondrial disease.

Exercise intolerance

10.1038/srep10480

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Patients with MELAS with negative myopathology for characteristic ragged-red fibers

Journal of the Neurological Sciences (2019)

Yuanyuan Lu Jianwen Deng Yuying Zhao Zhe Zhang Daojun Hong

MELAS syndrome

Lactic acidosis

Mitochondrial Encephalomyopathies

Mitochondrial disease

10.1016/j.jns.2019.116499

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Citations (11)

De novo frameshift variant in MT-ND1 causes a mitochondrial complex I deficiency associated with MELAS syndrome

Gene (2023)

Xiaoting Lou Yuwei Zhou Zhimei Liu Yaojun Xie Luyi Zhang

Mitochondrial disease

10.1016/j.gene.2023.147229

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YY1 Promotes Pancreatic Cancer Cell proliferation by Enhancing Mitochondrial Respiration

Research Square (Research Square) (2022)

Minghua Jiang Bin Li Junyi Wang Jing Liao Minghui Wu

Abstract KRAS -driven metabolic reprogramming is one of the key features of pancreatic ductal adenocarcinoma (PDAC) cells; however, the metabolic roles of other oncogenic genes, such as YY1 , in PDAC development are still unclear. In this study, we observed that YY1 expression was significantly elevated in human PDAC tissues and was positively correlated with a poor disease progression. Further, in vitro studies confirmed that YY1 deletion inhibited PDAC cell proliferation and tumorigenicity. Moreover, YY1 deletion also led to impaired mitochondrial RNA expression, which further induced mitochondrial oxidative phosphorylation (OXPHOS) complex assembly deficiency and altered cellular nucleotide homeostasis. Mechanistically, the impairment of mitochondrial OXPHOS function lowered the generation of aspartate, an output of the tricarboxylic acid cycle (TCA) and resulted in the inhibition of cell proliferation, owing to the absence of aspartate-associated nucleotide availability. Conversely, exogenous supplementation with aspartate fully restored PDAC cell proliferation. Altogether, our findings suggested that YY1 promotes PDAC cell proliferation by enhancing mitochondrial respiration and the TCA, which favors aspartate-associated nucleotide synthesis. These findings indicate that targeting nucleotide biosynthesis is a promising strategy for PDAC treatment.

10.21203/rs.3.rs-1466742/v1

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Citations (1)

Redefining the roles of mitochondrial DNA-encoded subunits in respiratory Complex I assembly

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2015)

Rasika Vartak Janice Deng Hezhi Fang Yidong Bai

Mitochondrial matrix

Mitochondrial respiratory chain

10.1016/j.bbadis.2015.04.008

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Citations (20)