2. Academic Validation
  3. Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy

Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy

  • Sci Adv. 2025 Apr 11;11(15):eadu5511. doi: 10.1126/sciadv.adu5511.
James T Hagen 1 2,  McLane M Montgomery 1 2 3,  Raphael T Aruleba 3,  Brett R Chrest 3,  Polina Krassovskaia 3,  Thomas D Green 3,  Emely A Pacheco 3,  Miki Kassai 2,  Tonya N Zeczycki 4,  Cameron A Schmidt 2 5,  Debajit Bhowmick 6,  Su-Fern Tan 7 8,  David J Feith 7 8,  Charles E Chalfant 7 8 9 10,  Thomas P Loughran Jr 7 8,  Darla Liles 11,  Mark D Minden 12,  Aaron D Schimmer 12,  Md Salman Shakil 13 14,  Matthew J McBride 13 14,  Myles C Cabot 2 4,  Joseph M McClung 15,  Kelsey H Fisher-Wellman 3
Affiliations

Affiliations

  • 1 Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
  • 2 East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA.
  • 3 Department of Cancer Biology, Atrium Health Wake Forest Baptist Comprehensive Cancer, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
  • 4 Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
  • 5 Department of Biology, East Carolina University, Greenville, NC, USA.
  • 6 Brody School of Medicine at East Carolina University, Flow Cytometry Core, Greenville, NC, USA.
  • 7 Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 8 University of Virginia Cancer Center, Charlottesville, VA, USA.
  • 9 Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.
  • 10 Research Service, Richmond Veterans Administration Medical Center, Richmond, VA, USA.
  • 11 Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
  • 12 Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
  • 13 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
  • 14 Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ, USA.
  • 15 Section of Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
PMID: 40203117 DOI: 10.1126/sciadv.adu5511
Abstract

OxPhos inhibitors have struggled to show a clinical benefit because of their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to acute myeloid leukemia (AML) mitochondria. Unlike healthy cells that couple respiration to ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix ATP consumption allows cells to survive bioenergetic stress. Thus, we hypothesized AML cells may resist chemotherapy-induced cell death by reversing the ATP Synthase reaction. In support, Bcl-2 inhibition with venetoclax abolished OxPhos flux without affecting mitochondrial polarization. In surviving AML cells, sustained mitochondrial polarization depended on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to down-regulations in the endogenous F1-ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. These data identify matrix ATP consumption as a Cancer cell-intrinsic bioenergetic vulnerability actionable in the context of Bcl-2 targeted chemotherapy.

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