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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 (UPR\n                    <jats:sup>mt<\/jats:sup>\n                    ), a stress-activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPR\n                    <jats:sup>mt<\/jats:sup>\n                    protease LONP1 (Lon peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPR\n                    <jats:sup>mt<\/jats:sup>\n                    . 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 UPR\n                    <jats:sup>mt<\/jats:sup>\n                    protease LONP1 in buffering stress from mitochondrial protein import in AML.\n                  <\/jats:p>\n                  <jats:p\/>\n                  <jats:p>Compared to normal hematopoietic cells, AML cells upregulate mitochondrial protein import and are more reliant on the mitochondrial protease LONP1 to maintain mitochondrial protein solubility.<\/jats:p>","DOI":"10.1172\/jci196687","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T19:01:42Z","timestamp":1781636502000},"source":"Crossref","is-referenced-by-count":0,"title":["Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1"],"prefix":"10.1172","volume":"136","author":[{"given":"Matthew","family":"Tcheng","sequence":"first","affiliation":[{"name":"Princess Margaret Cancer 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