PXD051129

PXD051129 is an original dataset announced via ProteomeXchange.

Title	Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy
Description	Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, primarily stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of our hypothesis, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well the endogenous F1-ATPase inhibitor ATP5IF1. In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy.
HostingRepository	jPOST
AnnounceDate	2025-04-02
AnnouncementXML	Submission_2025-04-01_08:00:05.322.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kelsey Fisher-Wellman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	S-carboxamidomethyl-L-cysteine; L-methionine sulfoxide
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-04-01 11:14:38	ID requested
⏵ 1	2025-04-01 08:00:05	announced

Dataset with its publication pending

submitter keyword: AML, ATP synthase, OxPhos, ATPIF1, Venetoclax, BCL-2

Kelsey Fisher-Wellman
lab head
Kelsey Fisher-Wellman
contact affiliation	East Carolina Diabetes and Obesity Institute
dataset submitter

jPOST dataset URI

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