内在的 OXPHOS 限制是白血病细胞生物能学的基础,eLife

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内在的 OXPHOS 限制是白血病细胞生物能学的基础
eLife ( IF 6.4 ) Pub Date : 2021-06-16 , DOI: 10.7554/elife.63104
Margaret Am Nelson _{1,

2} , Kelsey L McLaughlin _{1,

2} , James T Hagen _{1,

2} , Hannah S Coalson _{1,

2} , Cameron Schmidt _{1,

2} , Miki Kassai _{2,

3} , Kimberly A Kew ₃ , Joseph M McClung _{1,

2,

4} , P Darrell Neufer ₂ , Patricia Brophy ₂ , Nasreen A Vohra ₅ , Darla Liles ₆ , Myles C Cabot _{2,

3} , Kelsey H Fisher-Wellman _{1,

2}

Affiliation

以氧化磷酸化 (OXPHOS) 为代表的线粒体催化多种细胞过程，这些过程似乎对恶性生长至关重要。因此，人们对癌症中的线粒体代谢非常感兴趣。然而，尽管针对突变脱氢酶活性的药物很少，但几乎所有有希望的“线粒体疗法”都无法区分癌性和非癌性 OXPHOS，因此治疗指数有限。本项目的前提是，开发有效的线粒体靶向抗癌化合物需要回答两个基本问题：1）癌细胞和非癌细胞之间的线粒体生物能学实际上是否不同？2）如果是这样，其基本机制是什么？这些信息对于包括急性髓系白血病（AML）在内的人类癌症亚型尤其重要，其中线粒体代谢的改变与癌症生物学的各个方面（例如克隆扩张和化疗耐药）有关。在此，我们利用内部诊断生化工作流程来全面评估各种血液细胞类型的线粒体生物能效率和能力，特别关注 AML 中的 OXPHOS 动力学。与之前的报道一致，克隆细胞扩张是白血病的特征，普遍与代谢亢进表型相关，其中包括基础和最大糖酵解和呼吸通量的增加。然而，尽管每个细胞的线粒体数量增加了近 2 倍，但克隆扩增的造血干细胞、白血病母细胞以及化疗耐药性 AML 都始终以氧化 ATP 合成（即 OXPHOS）的内在限制为标志。_{值得注意的是，通过在 ATP 自由能（即 ΔG ATP} ）的生理范围内进行实验，我们提供了直接证据，表明白血病线粒体特别容易消耗_{ATP ，而不是细胞 ΔG ATP 。}与 AML 生物学相关，OXPHOS 动力学的急性恢复被证明对白血病原始细胞具有高度细胞毒性，表明主动 OXPHOS 抑制支持 AML 中的侵袭性疾病传播。总而言之，这些发现反对 ATP 是白血病中线粒体的主要输出，并提供了原理证明，即恢复而不是破坏癌症中的 OXPHOS 和/或细胞 ΔG ATP 可能代表了一种尚未开发的治疗血液恶性肿瘤和癌症的治疗_途径。化学耐药性。

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Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia

Typified by oxidative phosphorylation (OXPHOS), mitochondria catalyze a wide variety of cellular processes seemingly critical for malignant growth. As such, there is considerable interest in targeting mitochondrial metabolism in cancer. However, notwithstanding the few drugs targeting mutant dehydrogenase activity, nearly all hopeful 'mito-therapeutics' cannot discriminate cancerous from non-cancerous OXPHOS and thus suffer from a limited therapeutic index. The present project was based on the premise that the development of efficacious mitochondrial-targeted anti-cancer compounds requires answering two fundamental questions: 1) is mitochondrial bioenergetics in fact different between cancer and non-cancer cells? and 2) If so, what are the underlying mechanisms? Such information is particularly critical for the subset of human cancers, including acute myeloid leukemia (AML), in which alterations in mitochondrial metabolism are implicated in various aspects of cancer biology (e.g., clonal expansion and chemoresistance). Herein, we leveraged an in-house diagnostic biochemical workflow to comprehensively evaluate mitochondrial bioenergetic efficiency and capacity in various hematological cell types, with a specific focus on OXPHOS dynamics in AML. Consistent with prior reports, clonal cell expansion, characteristic of leukemia, was universally associated with a hyper-metabolic phenotype which included increases in basal and maximal glycolytic and respiratory flux. However, despite having nearly 2-fold more mitochondria per cell, clonally expanding hematopoietic stem cells, leukemic blasts, as well as chemoresistant AML were all consistently hallmarked by intrinsic limitations in oxidative ATP synthesis (i.e., OXPHOS). Remarkably, by performing experiments across a physiological span of ATP free energy (i.e, ΔG_ATP), we provide direct evidence that, rather than contributing to cellular ΔG_ATP, leukemic mitochondria are particularly poised to consume ATP. Relevant to AML biology, acute restoration of OXPHOS kinetics proved highly cytotoxic to leukemic blasts, suggesting that active OXPHOS repression supports aggressive disease dissemination in AML. Taken together, these findings argue against ATP being the primary output of mitochondria in leukemia and provide proof-of-principle that restoring, rather than disrupting, OXPHOS and/or cellular ΔG_ATP in cancer may represent an untapped therapeutic avenue for combatting hematological malignancy and chemoresistance.

更新日期：2021-06-16

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