Abstract

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, ΔGATP), we provide direct evidence that, rather than contributing to cellular ΔGATP, 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 ΔGATP in cancer may represent an untapped therapeutic avenue for combatting hematological malignancy and chemoresistance.

Data availability

All data from the manuscript are available upon request. In addition, all data are available in the source data files provided with this paper. Raw data for proteomics experiments are available online using accession number "PXD020715" for Proteome Xchange and accession number "JPST000934" for jPOST Repository.

Article and author information

Author details

  1. Margaret A M Nelson

    Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kelsey L McLaughlin

    Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. James T Hagen

    Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Hannah S Coalson

    Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Cameron Schmidt

    Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Miki Kassai

    Biochemistry & Molecular Biology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kimberly A Kew

    Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Joseph M McClung

    Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. P Darrell Neufer

    Biochemistry & Molecular Biology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Patricia Brophy

    Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Nasreen A Vohra

    Surgery, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Darla Liles

    Internal Medicine, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Myles C Cabot

    Biochemistry and Molecular Biology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Kelsey H Fisher-Wellman

    Physiology, East Carolina University, Greenville, United States
    For correspondence
    fisherwellmank17@ecu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0300-829X

Funding

U.S. Army Medical Research and Development Command (W81XWH-19-1-0213)

  • Kelsey H Fisher-Wellman

National Cancer Institute (P01 CA171983)

  • Myles C Cabot

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: All procedures involving human subjects were approved by the Institutional Review Board of the Brody School of Medicine at East Carolina University (study ID: UMCIRB 18-001328, UMCIRB 19-002331). For PBMC samples, healthy subjects (ages 18-70 years), without a prior history of hematological malignancy, were recruited from the surrounding area. Following informed consent (study ID: UMCIRB 18-001328), venous blood from the brachial region of the upper arm was collected. For primary leukemia samples, bone marrow aspirates were collected from patients undergoing confirmatory diagnosis for a range of hematological malignancies as a component of an already scheduled procedure. All patients provided informed consent prior to study enrollment (study ID: UMCIRB 19-002331).

Reviewing Editor

  1. Ivan Topisirovic, Jewish General Hospital, Canada

Publication history

  1. Received: September 15, 2020
  2. Accepted: June 16, 2021
  3. Accepted Manuscript published: June 16, 2021 (version 1)
  4. Version of Record published: June 23, 2021 (version 2)

Copyright

© 2021, Nelson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Margaret A M Nelson
  2. Kelsey L McLaughlin
  3. James T Hagen
  4. Hannah S Coalson
  5. Cameron Schmidt
  6. Miki Kassai
  7. Kimberly A Kew
  8. Joseph M McClung
  9. P Darrell Neufer
  10. Patricia Brophy
  11. Nasreen A Vohra
  12. Darla Liles
  13. Myles C Cabot
  14. Kelsey H Fisher-Wellman
(2021)
Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia
eLife 10:e63104.
https://doi.org/10.7554/eLife.63104
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