Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation
Abstract
Abstract Patients with acute myeloid leukemia (AML) have a poor 5-year survival rate, highlighting the need for the identification of new approaches to target this disease. AML is highly dependent on glutathione (GSH) metabolism for survival. Although the metabolic role of GSH is well characterized in AML, the contribution of protein glutathionylation, a reversible modification that protects protein thiols from oxidative damage, remains largely unexplored. Therefore, we sought to elucidate the role of protein glutathionylation in AML pathogenesis. Here, we demonstrate that protein glutathionylation is essential for AML cell survival. Specifically, the loss of glutaredoxin 2 (GLRX2), an enzyme that removes GSH modifications, resulted in selective primary AML cell death while sparing normal human hematopoietic stem and progenitor cells. Unbiased proteomic analysis revealed increased mitochondrial protein glutathionylation upon GLRX2 depletion, accompanied by mitochondrial dysfunction, including impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and increased opening of the mitochondrial permeability transition pore (mPTP). Further investigation identified adenosine triphosphate synthase subunit O (ATP5PO), a key regulator of mPTP opening and a component of the ATP synthase complex, as a critical GLRX2 target. Disruption of ATP5PO glutathionylation partially restored mPTP function and rescued AML cell viability after GLRX2 depletion. Moreover, both genetic and pharmacological inhibition of mPTP opening restored the leukemic potential of primary AML specimens in the absence of GLRX2. By disrupting glutathionylation-dependent mitochondrial homeostasis, this study reveals a novel vulnerability in AML that could inform future therapeutic strategies.
Article Details
Authors (28)
Tianyi Ling
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Cristiana O’Brien
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Jonathan R. St-Germain
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Vincent Rondeau
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Mary Shi
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Jacob M. Berman
Adrianna Cepa
3Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Paula Saez Raez
3Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Mark Wunderlich
Katharine M. Carter
3Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Cody Stillwell
3Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Christina Sexton
3Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Rachel Culp-Hill
7Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO
Julie A. Reisz
Saeer A. Adeel
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Andy G. X. Zeng
Suraj Bansal
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Emily Tsao
University of Toronto, Toronto, Ontario, Canada
He Tian Chen
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
John E. Dick
Mark D. Minden
Princess Margaret Cancer Centre, University Health Network
Andrea Arruda
Princess Margaret Cancer Centre, University Health Network
Maria L. Amaya
9Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
Anastasia N. Tikhonova
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Kristin J. Hope
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Angelo D’Alessandro
Brian Raught
Courtney L. Jones
12Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH