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 A. Reed, Bing Z. Carter, Michael Andreeff, Steven M. Kornblau, Mark D. Minden, Siavash Vahidi, Aaron D. Schimmer
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 A. Reed, Bing Z. Carter, Michael Andreeff, Steven M. Kornblau, Mark D. Minden, Siavash Vahidi, Aaron D. Schimmer
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Research Article Cell biology Metabolism Oncology

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

Abstract

Most mitochondrial proteins are nucleus-encoded, translated in the cytosol, and imported into the mitochondria. Through gene expression analysis and functional assays, we demonstrated that mitochondrial protein import was increased in acute myeloid leukemia (AML) cells compared with normal hematopoietic cells. Increased mitochondrial protein import was positively correlated with an increase in the mitochondrial unfolded protein response (UPRmt), a stress-activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPRmt protease LONP1 (Lon peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPRmt. Genetic or chemical inhibition of 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 UPRmt protease LONP1 in buffering stress from mitochondrial protein import in AML.

Authors

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 A. Reed, Bing Z. Carter, Michael Andreeff, Steven M. Kornblau, Mark D. Minden, Siavash Vahidi, Aaron D. Schimmer

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Figure 1

Mitochondrial protein import and the UPRmt are increased in a subset of primary AML, compared with normal hematopoietic cells.

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Mitochondrial protein import and the UPRmt are increased in a subset of ...
(A) Enrichment plot of nuclear-encoded mitochondrial gene expression in primary AML (n = 542) and normal mononuclear bone marrow hematopoietic cells (n = 73) from GSE13159. (B) Violin plot of mitochondrial protein import gene expression (GO 0072655) in primary AML and normal mononuclear bone marrow hematopoietic cells from GEO GSE13159. The midline represents the median value. ***P = 4.9 × 10–4 using an unpaired, 2-tailed Student’s t test. (C) Enrichment plot of mitochondrial protein import genes in primary AML from GSE13159, stratified by mitochondrial gene expression. (D) Primary AML and normal mononuclear bone marrow hematopoietic cells were treated with puromycin (1 μg/mL) for 7.5 minutes, fixed, stained with anti-puromycin, anti-TOMM40 (mitochondria) antibodies, and DAPI (nucleus). Colocalization of puromycin and TOMM40 was detected by a PLA and confocal microscopy. Representative cells are shown. Scale bars: 10 μm. (E) Mean ± SD PLA punctae per cell from D in primary AML cell samples (n = 5) and normal mononuclear bone marrow hematopoietic cells (n = 5), quantified using HALO software (n = 82–154 cells per sample). (F) Violin plot of UPRmt gene expression in primary AML and normal mononuclear bone marrow hematopoietic cells from GSE13159. ***P = 1.1 × 10–3 using an unpaired, 2-tailed Student’s t test. (G) Correlation analysis of UPRmt and mitochondrial protein import gene expression in primary AML samples from GSE13159. (H) Violin plot of LONP1 mRNA expression in primary AML and normal bone marrow hematopoietic cells from GSE13159. ****P = 6.9 × 10–5 using an unpaired, 2-tailed Student’s t test. (I) Expression of LONP1 protein in primary AML cells (n = 39), normal hematopoietic cells (n = 14), and CD34+ progenitors (n = 3) was measured in cell lysates by immunoblotting. Expression was quantified by densitometry and displayed relative to LONP1 protein levels in OCI-AML2 cells. See Supplemental Figure 5B, Supplemental Table 2 (patient cytogenetics). Data are presented as mean ± SD.