TY - JOUR
T1 - Mitochondrial regulation of GPX4 inhibition–mediated ferroptosis in acute myeloid leukemia
AU - Akiyama, Hiroki
AU - Zhao, Ran
AU - Ostermann, Lauren B.
AU - Li, Ziyi
AU - Tcheng, Matthew
AU - Yazdani, Samar J.
AU - Moayed, Arman
AU - Pryor, Malcolm L.
AU - Slngh, Sandeep
AU - Baran, Natalia
AU - Ayoub, Edward
AU - Nishida, Yuki
AU - Mak, Po Yee
AU - Ruvolo, Vivian R.
AU - Carter, Bing Z.
AU - Schimmer, Aaron D.
AU - Andreeff, Michael
AU - Ishizawa, Jo
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2023. corrected publication 2024.
PY - 2024/4
Y1 - 2024/4
N2 - Resistance to apoptosis in acute myeloid leukemia (AML) cells causes refractory or relapsed disease, associated with dismal clinical outcomes. Ferroptosis, a mode of non-apoptotic cell death triggered by iron-dependent lipid peroxidation, has been investigated as potential therapeutic modality against therapy-resistant cancers, but our knowledge of its role in AML is limited. We investigated ferroptosis in AML cells and identified its mitochondrial regulation as a therapeutic vulnerability. GPX4 knockdown induced ferroptosis in AML cells, accompanied with characteristic mitochondrial lipid peroxidation, exerting anti-AML effects in vitro and in vivo. Electron transport chains (ETC) are primary sources of coenzyme Q10 (CoQ) recycling for its function of anti–lipid peroxidation in mitochondria. We found that the mitochondria-specific CoQ potently inhibited GPX4 inhibition–mediated ferroptosis, suggesting that mitochondrial lipid redox regulates ferroptosis in AML cells. Consistently, Rho0 cells, which lack functional ETC, were more sensitive to GPX4 inhibition–mediated mitochondrial lipid peroxidation and ferroptosis than control cells. Furthermore, degradation of ETC through hyperactivation of a mitochondrial protease, caseinolytic protease P (ClpP), synergistically enhanced the anti-AML effects of GPX4 inhibition. Collectively, our findings indicate that in AML cells, GPX4 inhibition induces ferroptosis, which is regulated by mitochondrial lipid redox and ETC. (Figure presented.)
AB - Resistance to apoptosis in acute myeloid leukemia (AML) cells causes refractory or relapsed disease, associated with dismal clinical outcomes. Ferroptosis, a mode of non-apoptotic cell death triggered by iron-dependent lipid peroxidation, has been investigated as potential therapeutic modality against therapy-resistant cancers, but our knowledge of its role in AML is limited. We investigated ferroptosis in AML cells and identified its mitochondrial regulation as a therapeutic vulnerability. GPX4 knockdown induced ferroptosis in AML cells, accompanied with characteristic mitochondrial lipid peroxidation, exerting anti-AML effects in vitro and in vivo. Electron transport chains (ETC) are primary sources of coenzyme Q10 (CoQ) recycling for its function of anti–lipid peroxidation in mitochondria. We found that the mitochondria-specific CoQ potently inhibited GPX4 inhibition–mediated ferroptosis, suggesting that mitochondrial lipid redox regulates ferroptosis in AML cells. Consistently, Rho0 cells, which lack functional ETC, were more sensitive to GPX4 inhibition–mediated mitochondrial lipid peroxidation and ferroptosis than control cells. Furthermore, degradation of ETC through hyperactivation of a mitochondrial protease, caseinolytic protease P (ClpP), synergistically enhanced the anti-AML effects of GPX4 inhibition. Collectively, our findings indicate that in AML cells, GPX4 inhibition induces ferroptosis, which is regulated by mitochondrial lipid redox and ETC. (Figure presented.)
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U2 - 10.1038/s41375-023-02117-2
DO - 10.1038/s41375-023-02117-2
M3 - Article
C2 - 38148395
AN - SCOPUS:85180662436
SN - 0887-6924
VL - 38
SP - 729
EP - 740
JO - Leukemia
JF - Leukemia
IS - 4
ER -