Inhibition of PHB2/PINK1-mediated mitophagy potentiates venetoclax activity in acute myeloid leukemia
Abstract
Acute myeloid leukemia (AML) cells are highly dependent on mitochondrial activity for survival, with this metabolic reliance driven in part by BCL-2, which is therapeutically targeted by venetoclax-based therapies. The regulation of mitochondrial dynamics in leukemic cells is therefore essential for maintaining mitochondrial homeostasis. However, the mechanisms that enable selective degradation of damaged mitochondria (mitophagy) are still poorly understood in AML. In this study, we sought to elucidate the role of PTEN-induced putative kinase 1 (PINK1), a key sensor of mitochondrial stress, in regulating mitophagy in leukemic cells. Our results identified PINK1 as a central modulator of mitophagy. Genetic depletion of PINK1 reduced both basal and stress-induced mitophagy, leading to mitochondria accumulation and functional impairment. Additionally, we discovered that PINK1 stabilization during mitochondrial stress is regulated by Prohibitin 2 (PHB2), and that depletion or inhibition of PHB2 mirrored the biological effects of PINK1 loss. Notably, both genetic depletion of PINK1 or PHB2, as well as pharmacological inhibition of PHB2, significantly increased AML cell sensitivity to venetoclax both in vitro and in vivo. Together, these findings highlight the potential of targeting the PHB2/PINK1 signalling pathway to improve the efficacy of venetoclax-based therapies in AML by disrupting the mitophagy process.
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BibTeX
@article{vazquez2026inhibition,
title = {{Inhibition of PHB2/PINK1-mediated mitophagy potentiates venetoclax activity in acute myeloid leukemia}},
author = {Romain Vazquez and Maxime Sajot and Jad Nasrallah and Rudy Birsen and Ismaël Boussaid and Morgane Plevenage and Zubaidan Tuerdi and Axelle Guedon and Lilia Cantero Aguilar and Tony Huynh and Natacha Johnson and Chloé Friedrich and Eric Grignano and Justine Decroocq and Lise Willems and Carole Almire and Marie-Clotilde Alves-Guerra and Evelyne Lauret and Yannick Simoni and Michaela Fontenay and Olivier Kosmider and Didier Bouscary and Clement Larrue and Nicolas Chapuis},
journal = {Leukemia},
year = {2026},
month = oct,
doi = {10.1038/s41375-026-03160-5},
url = {https://hal.science/hal-05852553v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Inhibition of PHB2/PINK1-mediated mitophagy potentiates venetoclax activity in acute myeloid leukemia
AU - Romain Vazquez
AU - Maxime Sajot
AU - Jad Nasrallah
AU - Rudy Birsen
AU - Ismaël Boussaid
AU - Morgane Plevenage
AU - Zubaidan Tuerdi
AU - Axelle Guedon
AU - Lilia Cantero Aguilar
AU - Tony Huynh
AU - Natacha Johnson
AU - Chloé Friedrich
AU - Eric Grignano
AU - Justine Decroocq
AU - Lise Willems
AU - Carole Almire
AU - Marie-Clotilde Alves-Guerra
AU - Evelyne Lauret
AU - Yannick Simoni
AU - Michaela Fontenay
AU - Olivier Kosmider
AU - Didier Bouscary
AU - Clement Larrue
AU - Nicolas Chapuis
PY - 2026
DA - 2026/10/13
JO - Leukemia
DO - 10.1038/s41375-026-03160-5
UR - https://hal.science/hal-05852553v1
AB - Acute myeloid leukemia (AML) cells are highly dependent on mitochondrial activity for survival, with this metabolic reliance driven in part by BCL-2, which is therapeutically targeted by venetoclax-based therapies. The regulation of mitochondrial dynamics in leukemic cells is therefore essential for maintaining mitochondrial homeostasis. However, the mechanisms that enable selective degradation of damaged mitochondria (mitophagy) are still poorly understood in AML. In this study, we sought to elucidate the role of PTEN-induced putative kinase 1 (PINK1), a key sensor of mitochondrial stress, in regulating mitophagy in leukemic cells. Our results identified PINK1 as a central modulator of mitophagy. Genetic depletion of PINK1 reduced both basal and stress-induced mitophagy, leading to mitochondria accumulation and functional impairment. Additionally, we discovered that PINK1 stabilization during mitochondrial stress is regulated by Prohibitin 2 (PHB2), and that depletion or inhibition of PHB2 mirrored the biological effects of PINK1 loss. Notably, both genetic depletion of PINK1 or PHB2, as well as pharmacological inhibition of PHB2, significantly increased AML cell sensitivity to venetoclax both in vitro and in vivo. Together, these findings highlight the potential of targeting the PHB2/PINK1 signalling pathway to improve the efficacy of venetoclax-based therapies in AML by disrupting the mitophagy process.
SN - 0887-6924
SN - 1476-5551
ER -