Research Centre, CHU-Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada; Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada.
Proteomic Platform, IRIC Université de Montréal, Montreal, Quebec, Canada.
Metabolism. 2018 Aug;85:151-160. doi: 10.1016/j.metabol.2018.03.011. Epub 2018 Mar 18.
Childhood acute lymphoblastic leukemia (cALL) is the most prevalent form of cancer in children. Due to advances in treatment and therapy, young cALL subjects now achieve a 90% survival rate. However, this tremendous advance does not come without consequence since ~2/3 of cALL survivors are affected by long-term and late, severe complications. Although the metabolic syndrome is a very serious sequel of cALL, the mechanisms remain undefined. It is also surprising to note that the mitochondrion, a central organelle in metabolic functions and the main cellular energy generator, have not yet been explored.
To determine whether cALL survivors exhibit impairments in their mitochondrial functions and proteomic profiling in relationship with metabolic disorders in cALL survivors compared to healthy controls.
Anthropometric measures, metabolic characteristics and lipid profiles were assessed, mitochondria isolated from peripheral blood mononuclear cells, and proteomic analyzed. Our data demonstrated that metabolically. Unhealthy survivors exhibited several metabolic syndrome components (e.g. overweight, insulin resistance, dyslipidemia, inflammation) whereas Healthy cALL survivors resemble the Controls. In line with these abnormalities, functional experiments in these subjects revealed a significant decrease in the protein expression of mitochondrial antioxidant superoxide dismutase, PGC1-α transcription factor (a key modulator of mitochondrion biogenesis), and an increase in pro-apoptotic cytochrome c. Proteomic analysis of mitochondria by mass spectrometry revealed changes in the regulation of proteins related to inflammation, apoptosis, energy production, redox and antioxidant activity, fatty acid β-oxidation, protein transport and metabolism, and signalling pathways between groups.
Through the use of proteomic analysis, our work demonstrated a number of significant alterations in protein expression in mitochondria of cALL survivors, especially the metabolically Unhealthy survivor group. Further investigation of these proteins may help delineate the mechanisms by which mitochondrial dysfunctions exert cardiometabolic derangements in cALL survivors.
儿童急性淋巴细胞白血病（cALL）是儿童中最常见的癌症形式。由于治疗和疗法的进步，年轻的 cALL 患者现在的生存率达到了 90%。然而，这种巨大的进步并非没有代价，因为大约 2/3 的 cALL 幸存者受到长期和晚期严重并发症的影响。尽管代谢综合征是 cALL 的一个非常严重的后遗症，但其中的机制尚不清楚。令人惊讶的是，线粒体作为代谢功能的核心细胞器和主要的细胞能量发生器，尚未被探索。
确定 cALL 幸存者是否表现出线粒体功能障碍，并与代谢紊乱相关的蛋白质组学特征，与健康对照组相比。
评估了人体测量学指标、代谢特征和血脂谱，从外周血单核细胞中分离出线粒体，并进行蛋白质组学分析。我们的数据表明，代谢不健康的幸存者表现出几种代谢综合征成分（如超重、胰岛素抵抗、血脂异常、炎症），而健康的 cALL 幸存者则与对照组相似。与这些异常相一致，这些受试者的功能实验显示线粒体抗氧化超氧化物歧化酶、PGC1-α 转录因子（线粒体生物发生的关键调节剂）的蛋白质表达显著减少，以及促凋亡细胞色素 c 的增加。通过质谱对线粒体进行蛋白质组学分析发现，与炎症、凋亡、能量产生、氧化还原和抗氧化活性、脂肪酸β-氧化、蛋白质转运和代谢以及信号通路相关的蛋白质的调节在各组之间发生了变化。
通过蛋白质组学分析，我们的工作表明 cALL 幸存者的线粒体蛋白质表达发生了许多显著变化，特别是代谢不健康的幸存者组。进一步研究这些蛋白质可能有助于阐明线粒体功能障碍在 cALL 幸存者中导致心脏代谢紊乱的机制。
