Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1

Matthew Tcheng; Veronique Voisin; Geethu Emily Thomas; Anastasija A. Piric; Marcela Gronda; Rose Hurren; Dakai Ling; Yongran Yan; Lan Xin Zhang; Yue Feng; Ali Chegini; Nathan Duong; Ross S. Mancini; Stefan Quinn W. Currie; Zaynab Mamai; Brady Stock; Shahbaz Khan; Yulia Jitkova; Chaitra Sarathy; Edward Ayoub; Po Yee Mak; Andrea Arruda; Thomas Kislinger; Mark Reed; Bing Z. Carter; Michael Andreeff; Steven M. Kornblau; Mark D. Minden; Siavash Vahidi; Aaron D. Schimmer

doi:10.1172/JCI196687

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Tcheng, M. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Hurren, R. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Ling, D. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Yan, Y. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Zhang, L. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Feng, Y. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Chegini, A. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

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¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Currie, S. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Mamai, Z. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Stock, B. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Khan, S. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Jitkova, Y. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Sarathy, C. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Ayoub, E. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Mak, P. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Arruda, A. in: PubMed | Google Scholar |

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Kislinger, T. in: PubMed | Google Scholar |

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Reed, M. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Carter, B. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Andreeff, M. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Kornblau, S. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Minden, M. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Vahidi, S. in: PubMed | Google Scholar

¹Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

²Krembil Brain Institute, University Health Network, Toronto, Canada

³Department of Molecular and Cell Biology, University of Guelph, Guelph, Canada

⁴Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Schimmer, A. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI196687.
Copyright © 2026, Tcheng et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 16, 2026 - Version history

Most mitochondrial proteins are nuclear encoded, translated in the cytosol, and imported into the mitochondria. Through gene expression analysis and functional assays, we demonstrated that mitochondrial protein import is increased in acute myeloid leukemia (AML) cells compared to normal hematopoietic cells. Increased mitochondrial protein import was positively correlated with increased mitochondrial unfolded protein response (UPR^mt), a stress activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPR^mt protease LONP1 (Lon Peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPR^mt. Genetically or chemically inhibiting the LONP1 ATPase domain induced mitochondrial protein aggregation and selectively killed AML cells with high LONP1 expression while sparing AML cells with low LONP1 expression and normal hematopoietic cells in vitro and in vivo. Thus, we uncovered a critical role of the UPR^mt protease LONP1 in buffering stress from mitochondrial protein import in AML.

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Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1

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