Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia

eLife

Kimberly A Kew¹  Darla Liles²  Margaret AM Nelson³  Kelsey H Fisher-Wellman³  James T Hagen³  Hannah S Coalson³  Cameron Schmidt³  Kelsey L McLaughlin³  Joseph M McClung⁴  Nasreen A Vohra⁵  P Darrell Neufer⁶  Patricia Brophy⁶  Myles C Cabot⁷  Miki Kassai⁷ 

[1] Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, United States;Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, United States;Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, United States;East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, United States;Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, United States;East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, United States;Department of Cardiovascular Sciences, Brody School of Medicine, East Carolina University, Greenville, United States;Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, United States;East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, United States;East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, United States;Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, United States;

关键词: mitochondria;    cancer bioenergetics;    OXPHOS;    acute myeloid leukemia;    mitochondrial proteomics;    Human;   

DOI  :  10.7554/eLife.63104

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Currently there is great interest in targeting mitochondrial oxidative phosphorylation (OXPHOS) in cancer. However, notwithstanding the targeting of mutant dehydrogenases, nearly all hopeful ‘mito-therapeutics’ cannot discriminate cancerous from non-cancerous OXPHOS and thus suffer from a limited therapeutic index. Using acute myeloid leukemia (AML) as a model, herein, we leveraged an in-house diagnostic biochemical workflow to identify ‘actionable’ bioenergetic vulnerabilities intrinsic to cancerous mitochondria. Consistent with prior reports, AML growth and proliferation was associated with a hyper-metabolic phenotype which included increases in basal and maximal respiration. 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 OXPHOS limitations. Remarkably, by performing experiments across a physiological span of ATP free energy, we provide direct evidence that leukemic mitochondria are particularly poised to consume ATP. Relevant to AML biology, acute restoration of oxidative ATP synthesis proved highly cytotoxic to leukemic blasts, suggesting that active OXPHOS repression supports aggressive disease dissemination in AML. Together, these findings argue against ATP being the primary output of leukemic mitochondria and provide proof-of-principle that restoring, rather than disrupting, OXPHOS may represent an untapped therapeutic avenue for combatting hematological malignancy and chemoresistance.

【 授权许可】

CC BY