Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis-associated cancer

Background:Mitochondria are key regulators in cell proliferation and apoptosis.Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis.This study aimed to investigate whether mitochondrial transcription factor A(TFAM),a key regulator of mitochondrial DNA transcription and replication,is involved in the initiation and progression of colitis-associated cancer(CAC).Methods:TFAM expression was examined in tissue samples of inflammatory bowel diseases(IBD)and CAC by immunohistochemistry.Intestinal epithelial cell(IEC)-specific TFAM-knockout mice(TFAM^(△IEC))and colorectal cancer(CRC)cells with TFAM knockdown or overexpression were used to evaluate the role of TFAMin colitis and the initiation and progression ofCAC.The underlying mechanisms of TFAMwere also explored by analyzingmitochondrial respiration function and biogenesis.Results:The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity.The downregulation of TFAM in IECs was induced by interleukin-6 in a signal transducer and activator of transcription 3(STAT3)/miR-23b-dependent manner.In addition,TFAM knockout impaired IECturnover to promote dextran sulfate sodium(DSS)-induced colitis inmice.Of note,TFAMknockout increased the susceptibility of mice to azoxymethane/DSSinduced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis-associated tumorigenesis.By contrast,TFAM expression was upregulated in CAC tissues and contributed to cell growth.Furthermore,it was demonstrated that β-catenin induced the upregulation of TFAM through c-Myc in CRC cells.Mechanistically,TFAMpromoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity.Conclusions:TFAM plays a dual role in the initiation and progression of CAC,providing a novel understanding of CAC pathogenesis.

Activation of G-protein-coupled receptor 39 reduces neuropathic pain in a rat model

Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.

Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer＇s disease

Alzheimer’s disease （AD） is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.

线粒体转录因子A在炎症相关结直肠癌的发生和进展阶段的双向作用

背景与目的线粒体是细胞增殖和凋亡的关键调节因子。线粒体功能的改变与炎症和肿瘤发生密切相关。线粒体转录因子A(mitochondrial transcription factor A,TFAM)是线粒体DNA转录和复制的重要调节因子,本文旨在研究其是否参与炎症相关结直肠癌(colitis-associated cancer,CAC)的发生和进展。方法通过免疫组织化学法检测炎性肠病(inflammatory bowel diseases,IBD)和CAC组织样本中TFAM的表达情况。用肠上皮细胞(intestinal epithelial cell,IEC)TFAM特异性敲除小鼠(TFAM△IEC)和TFAM敲低或过表达的结直肠癌(colorectal cancer,CRC)细胞评估TFAM在肠炎及CAC的发生和进展中的作用。通过分析线粒体呼吸功能和生物发生探讨TFAM的潜在作用机制。结果TFAM在人活动性IBD中表达下调,与疾病活动度呈负相关。在IEC中IL-6通过调控信号转导和转录激活因子3(signal transducer and activator of transcription 3,STAT3)/miR-23b通路轴下调TFAM表达。此外,TFAM敲除可影响IEC再生,从而加剧葡聚糖硫酸钠(dextran sulfate sodium,DSS)诱导的小鼠肠炎症状。值得注意的是,TFAM敲除可促进偶氮甲烷/DSS诱导的小鼠CAC的发生,TFAM过表达可抑制模型小鼠肠炎和炎症相关结直肠癌的发生。TFAM在CAC组织中表达上调并促进细胞生长。在CRC细胞中β-连环蛋白通过调控c-Myc促进TFAM表达上调。在机制上,TFAM通过增加线粒体的生物发生和活性来促进IEC和CRC细胞增殖。结论TFAM在CAC的发生和进展的不同阶段发挥不同的作用,为CAC发病机制的研究提供了新数据。