Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy
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 F<sub>1</sub>-ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F<sub>1</sub>-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.
Authors
- McLane M. Montgomery (ORCID: https://orcid.org/0000-0002-8253-6858)
- Charles E. Chalfant (ORCID: https://orcid.org/0000-0002-5844-5235)
- Md Salman Shakil (ORCID: https://orcid.org/0000-0002-8922-9500)
- Polina Krassovskaia (ORCID: https://orcid.org/0000-0002-6271-3036)
- Tonya N. Zeczycki (ORCID: https://orcid.org/0000-0002-5216-1960)
- Mark D. Minden (ORCID: https://orcid.org/0000-0002-9089-8816)
- Raphael Taiwo Aruleba (ORCID: https://orcid.org/0000-0003-0879-344X)
- Su‐Fern Tan (ORCID: https://orcid.org/0000-0002-8301-0823)
- Myles C. Cabot
- Darla Liles (ORCID: https://orcid.org/0000-0003-1480-7887)
- Joseph M. McClung (ORCID: https://orcid.org/0000-0002-9789-0454)
- Thomas D. Green
- Aaron David Schimmer (ORCID: https://orcid.org/0000-0003-4023-3899)
- Kelsey H. Fisher‐Wellman (ORCID: https://orcid.org/0000-0002-0300-829X)
- Matthew J. McBride (ORCID: https://orcid.org/0000-0001-9846-3385)
- Debajit Bhowmick (ORCID: https://orcid.org/0000-0002-4905-569X)
- David J. Feith (ORCID: https://orcid.org/0000-0003-4981-1691)
- Cameron A. Schmidt (ORCID: https://orcid.org/0000-0001-6628-6329)
- Miki Kassai
- James T. Hagen (ORCID: https://orcid.org/0000-0002-0587-5370)
- Brett R. Chrest (ORCID: https://orcid.org/0009-0006-0936-7660)
- Thomas P. Loughran (ORCID: https://orcid.org/0000-0001-6612-1428)
- Emely A. Pacheco
Institutions
- Rutgers, The State University of New Jersey (US)
- Atrium Health Wake Forest Baptist (US)
- United States Department of Veterans Affairs (US)
- University Health Network (CA)
- East Carolina University (US)
- Princess Margaret Cancer Centre (CA)
- Rutgers Sexual and Reproductive Health and Rights (NL)
- University of Virginia Cancer Center
- Wake Forest University (US)
- University of Virginia (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-04-09
- DOI
- https://doi.org/10.1126/sciadv.adu5511
- Citations
- 14
- Primary Topic
- ATP Synthase and ATPases Research
- Type
- article
- Field-Weighted Citation Impact
- 11.28