机构：[1]Neuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Bergen, Norway[2]Department of Clinical Medicine, University of Bergen, Bergen, Norway[3]Leiden University Medical Centre, Leiden University, Leiden, The Netherlands[4]Department of Biomedicine, University of Bergen, Bergen, Norway[5]Department of Medicine, Haukeland University Hospital, Bergen, Norway[6]State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China[7]Department of Head and Neck Cancer Surgery, West China School of Stomatology, Sichuan University, Chengdu, China[8]Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway[9]Norwegian Center for Stem Cell Research, Oslo University Hospital and University of Oslo, Oslo, Norway[10]Institute of Immunology, Oslo University Hospital, Oslo, Norway[11]Hybrid Technology Hub ‐ Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway[12]Department of Pediatric Research, Oslo University Hospital, Oslo, Norway
Mutations in POLG disrupt mtDNA replication and cause devastating diseases often with neurological phenotypes. Defining disease mechanisms has been hampered by limited access to human tissues, particularly neurons. Using patient cells carrying POLG mutations, we generated iPSCs and then neural stem cells. These neural precursors manifested a phenotype that faithfully replicated the molecular and biochemical changes found in patient post-mortem brain tissue. We confirmed the same loss of mtDNA and complex I in dopaminergic neurons generated from the same stem cells. POLG-driven mitochondrial dysfunction led to neuronal ROS overproduction and increased cellular senescence. Loss of complex I was associated with disturbed NAD+ metabolism with increased UCP2 expression and reduced phosphorylated SirT1. In cells with compound heterozygous POLG mutations, we also found activated mitophagy via the BNIP3 pathway. Our studies are the first that show it is possible to recapitulate the neuronal molecular and biochemical defects associated with POLG mutation in a human stem cell model. Further, our data provide insight into how mitochondrial dysfunction and mtDNA alterations influence cellular fate determining processes.
基金：
Norwegian Research Council (project no. 229652), Rakel og Otto Kr.Bruuns legat and Meltzer (project no. 809432). GJS was partly supported by the Norwegian Research Council through its Centres of Excellence funding scheme (project number 262613).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2020]版：
大类|1 区医学
小类|1 区医学：研究与实验
最新[2023]版：
大类|1 区医学
小类|1 区医学：研究与实验
第一作者：
第一作者机构：[1]Neuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Bergen, Norway[2]Department of Clinical Medicine, University of Bergen, Bergen, Norway
共同第一作者：
通讯作者：
通讯机构：[1]Neuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Bergen, Norway[2]Department of Clinical Medicine, University of Bergen, Bergen, Norway
推荐引用方式(GB/T 7714)：
Kristina Xiao Liang,Cecilie Katrin Kristiansen,Sepideh Mostafavi,et al.Disease-specific phenotypes in iPSC-derived neural stem cells with POLG mutations.[J].EMBO molecular medicine.2020,12(10):e12146.doi:10.15252/emmm.202012146.
APA：
Kristina Xiao Liang,Cecilie Katrin Kristiansen,Sepideh Mostafavi,Guro Helén Vatne,Gina Alien Zantingh...&Laurence A Bindoff.(2020).Disease-specific phenotypes in iPSC-derived neural stem cells with POLG mutations..EMBO molecular medicine,12,(10)
MLA：
Kristina Xiao Liang,et al."Disease-specific phenotypes in iPSC-derived neural stem cells with POLG mutations.".EMBO molecular medicine 12..10(2020):e12146
医学