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Updated: May 15, 2025

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

James T Hagen1,2, McLane M Montgomery1,2,3, Raphael T Aruleba3

  • 1Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.

Science Advances
|April 9, 2025
PubMed

Insights

Acute myeloid leukemia (AML) cells uniquely consume ATP in mitochondria to maintain energy, enabling resistance to chemotherapy. Targeting this ATP consumption pathway offers a novel therapeutic strategy for AML treatment.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Oxidative phosphorylation (OxPhos) inhibitors face challenges in cancer therapy due to lack of specificity between healthy and cancerous cells.
  • Mitochondria play a crucial role in cellular energy metabolism and cancer cell survival.

Purpose of the Study:

  • To identify a unique bioenergetic mechanism in acute myeloid leukemia (AML) mitochondria.
  • To investigate the role of ATP consumption in AML cell resistance to chemotherapy, specifically BCL-2 inhibition.

Main Methods:

  • Investigated mitochondrial bioenergetics in AML cells.
  • Utilized BCL-2 inhibition with venetoclax to assess OxPhos flux and mitochondrial polarization.
  • Manipulated the expression of ATP5IF1 (F1-ATPase inhibitor) to determine its role in venetoclax resistance.

Main Results:

  • AML mitochondria consume ATP to maintain inner-membrane polarization, unlike healthy cells.
  • BCL-2 inhibition with venetoclax disrupted OxPhos but not mitochondrial polarization in AML cells.
  • Matrix ATP consumption was essential for AML cell survival under venetoclax treatment and was enhanced in resistant cells due to reduced ATP5IF1 levels.
  • ATP5IF1 knockdown conferred venetoclax resistance, while its overexpression increased sensitivity.

Conclusions:

  • Matrix ATP consumption represents a cancer cell-intrinsic vulnerability in AML.
  • Targeting this bioenergetic mechanism, in conjunction with BCL-2 inhibitors like venetoclax, presents a promising therapeutic strategy for AML.

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