2. Academic Validation
  3. A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential

A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential

  • Cell Rep. 2025 Nov 25;44(11):116496. doi: 10.1016/j.celrep.2025.116496.
Ting Liu 1,  Ji-Hao Zhou 2,  Yongbo Gong 1,  Ying Zhang 1,  Yongcan Ma 1,  Xiaowen Zhang 1,  Mohammad Minhajuddin 3,  Wenjie Song 1,  Zixuan Zhuang 1,  Ana Vujovic 3,  Youli Lu 4,  Ang Jia 1,  Rongqun Guo 5,  Ruobing Ren 1,  Lu Zhou 6,  Yu Xiong 7,  Linzhang Huang 1,  Xingrong Du 8,  Tong-Jin Zhao 1,  Peng Li 9,  Craig T Jordan 3,  Haobin Ye 10
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Drug Clinical Trial Center, Shanghai Xuhui Central Hospital / Zhongshan-Xuhui Hospital, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
  • 2 Department of Hematology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China.
  • 3 Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • 4 Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Institute of Clinical Mass Spectrometry, Shanghai Academy of Experimental Medicine, Shanghai, China.
  • 5 Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Academy of Medical Science, Henan Medical College of Zhengzhou University, Zhengzhou, Henan, China.
  • 6 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
  • 7 Obstetrics and Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
  • 8 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Drug Clinical Trial Center, Shanghai Xuhui Central Hospital / Zhongshan-Xuhui Hospital, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Institute of Clinical Mass Spectrometry, Shanghai Academy of Experimental Medicine, Shanghai, China.
  • 9 Tianjian Laboratory of Advanced Biomedical Sciences, School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China.
  • 10 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Drug Clinical Trial Center, Shanghai Xuhui Central Hospital / Zhongshan-Xuhui Hospital, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Institute of Clinical Mass Spectrometry, Shanghai Academy of Experimental Medicine, Shanghai, China. Electronic address: [email protected].
PMID: 41166305 DOI: 10.1016/j.celrep.2025.116496
Abstract

Targeting mitochondria emerges as a promising anti-leukemia strategy, yet selective mitochondrial disruption remains challenging. Here, we identified elevated mitochondrial membrane potential (MMP) as a hallmark of leukemic transformation and chemotherapy-resistant cells, prompting screening for MMP-targeting agents. Alexidine (AD), an MMP-depleting compound, demonstrated potent anti-leukemic activity with low toxicity. Mechanistically, AD binds unsaturated cardiolipin to destabilize the inner membrane localization of mitochondrial ribosome, suppressing cardiolipin-dependent mitochondrial translation, a process validated as an independent prognostic marker in leukemia. Interestingly, intercellular heterogeneity in mitochondrial translation drives heterogeneous MMP states within the population, which is associated with stemness and chemoresistance. Intriguingly, this intra-population MMP difference stems not from cardiolipin-mediated translation but from asparagine-driven mitochondrial protein synthesis-a mechanism leukemia cells selectively activate to evade chemotherapy. Critically, pharmacological asparagine depletion synergistically enhances chemosensitivity by disrupting this resistance pathway. Our findings establish that MMP regulation through cardiolipin-maintained homeostasis and asparagine-fueled adaptation represents therapeutic vulnerabilities, advocating co-targeting strategies to overcome resistance.

Keywords

CP: cancer; alexidine; asparagine; leukemia stem cells; mitochondrial membrane potential; mitochondrial translation.

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