Kingsbury Joanne M, Shamaprasad Nachiketha, Billmyre R Blake, Heitman Joseph, Cardenas Maria E
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
Hum Mol Genet. 2016 Aug 15;25(16):3524-3538. doi: 10.1093/hmg/ddw195. Epub 2016 Jul 17.
A major advance in understanding the progression and prognostic outcome of certain cancers, such as low-grade gliomas, acute myeloid leukaemia, and chondrosarcomas, has been the identification of early-occurring mutations in the NADP-dependent isocitrate dehydrogenase genes IDH1 and IDH2 These mutations result in the production of the onco-metabolite D-2-hydroxyglutarate (2HG), thought to contribute to disease progression. To better understand the mechanisms of 2HG pathophysiology, we introduced the analogous glioma-associated mutations into the NADPisocitrate dehydrogenase genes (IDP1, IDP2, IDP3) in Saccharomyces cerevisiae Intriguingly, expression of the mitochondrial IDP1 mutant allele results in high levels of 2HG production as well as extensive mtDNA loss and respiration defects. We find no evidence for a reactive oxygen-mediated mechanism mediating this mtDNA loss. Instead, we show that 2HG production perturbs the iron sensing mechanisms as indicated by upregulation of the Aft1-controlled iron regulon and a concomitant increase in iron levels. Accordingly, iron chelation, or overexpression of a truncated AFT1 allele that dampens transcription of the iron regulon, suppresses the loss of respirative capacity. Additional suppressing factors include overexpression of the mitochondrial aldehyde dehydrogenase gene ALD5 or disruption of the retrograde response transcription factor RTG1 Furthermore, elevated α-ketoglutarate levels also suppress 2HG-mediated respiration loss; consistent with a mechanism by which 2HG contributes to mtDNA loss by acting as a toxic α-ketoglutarate analog. Our findings provide insight into the mechanisms that may contribute to 2HG oncogenicity in glioma and acute myeloid leukaemia progression, with the promise for innovative diagnostic and prognostic strategies and novel therapeutic modalities.
在理解某些癌症（如低级别胶质瘤、急性髓系白血病和软骨肉瘤）的进展和预后结果方面取得的一项重大进展是，在依赖烟酰胺腺嘌呤二核苷酸磷酸（NADP）的异柠檬酸脱氢酶基因IDH1和IDH2中发现了早期发生的突变。这些突变导致致癌代谢物D-2-羟基戊二酸（2HG）的产生，据认为这有助于疾病进展。为了更好地理解2HG病理生理学的机制，我们将类似的胶质瘤相关突变引入酿酒酵母中的NADP-异柠檬酸脱氢酶基因（IDP1、IDP2、IDP3）。有趣的是，线粒体IDP1突变等位基因的表达导致高水平的2HG产生以及广泛的线粒体DNA（mtDNA）丢失和呼吸缺陷。我们没有发现活性氧介导的机制介导这种mtDNA丢失的证据。相反，我们表明，如Aft1控制的铁调节子上调和铁水平同时增加所表明的，2HG的产生扰乱了铁感应机制。因此，铁螯合或抑制铁调节子转录的截短AFT1等位基因的过表达可抑制呼吸能力的丧失。其他抑制因素包括线粒体醛脱氢酶基因ALD5的过表达或逆行反应转录因子RTG1的破坏。此外，升高的α-酮戊二酸水平也抑制2HG介导的呼吸丧失；这与2HG通过作为有毒的α-酮戊二酸类似物导致mtDNA丢失的机制一致。我们的研究结果为可能导致2HG在胶质瘤和急性髓系白血病进展中的致癌性的机制提供了见解，有望用于创新的诊断和预后策略以及新型治疗方式。
