The Journal of clinical investigation · 2026
Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
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Tcheng Matthew, Voisin Veronique, Thomas Geethu Emily, Piric Anastasija A, Gronda Marcela, Hurren Rose, Ling Dakai, Yan Yongran, Zhang Lan Xin, Feng Yue, Chegini Ali, Duong Nathan, Mancini Ross S, Currie Stefan Quinn W, Mamai Zaynab, Stock Brady, Khan Shahbaz, Jitkova Yulia, Sarathy Chaitra, Ayoub Edward, Mak Po Yee, Arruda Andrea, Kislinger Thomas, Reed Mark A, Carter Bing Z, Andreeff Michael, Kornblau Steven M, Minden Mark D, Vahidi Siavash, Schimmer Aaron D
Аннотация
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.