Abstract 3033: Increased mitochondrial protein import necessitates greater reliance on the mitochondrial unfolded protein response (UPRmt) and the protease LONP1 to maintain mitochondrial protein solubility and cell viability in acute myeloid leukemia (AML)
Bibliographic record
Abstract
Abstract Almost all mitochondrial proteins are encoded by nuclear DNA, translated in the cytosol, and imported into the mitochondria. Once inside the mitochondria, these unfolded, aggregation prone precursors are processed and folded into mature forms. Failure to properly process and fold these newly imported proteins results in the formation of toxic aggregates. To counter the mitochondrial stress from newly imported proteins, cells developed the mitochondrial unfolded protein response (UPRmt), a conserved pathway which activates the transcription of mitochondrial proteases and chaperones to fold newly imported precursors and degrade protein aggregates. There are no UPRmt gene sets in the KEGG, Gene Ontology or Reactome databases, so we compiled a 39-gene signature of the known components of the human UPRmt. In primary AML cells, expression of this UPRmt signature was increased compared to normal hematopoietic cells. UPRmt expression was strongly correlated with mitochondrial protein import expression, highlighting the protective role of the UPRmt in countering the stress of increased protein import. Leading edge analysis identified the protease LONP1 as a top driver of the UPRmt signature and analysis of AML cells’ dependency on UPRmt genes (Depmap) also identified LONP1 as a top essential gene. We focused additional studies on LONP1 and its role in protecting AML cells from mitochondrial stress. LONP1 mRNA expression was increased in AML compared to normal hematopoietic cells. LONP1 protein was increased >2-fold in 26/39 primary AML samples, compared to bulk (n=14) and CD34+ (n=3) hematopoietic cells. In AML, LONP1 expression positively correlated with expression of protein import and UPRmt genes as well as decreased overall survival. LONP1 folds newly imported precursors and degrades aggregated mitochondrial proteins. To assess the role of LONP1 in mitochondrial proteostasis, we developed a novel assay to measure mitochondrial protein aggregation. LONP1 genetic depletion and chemical inhibition with Omaveloxolone and bardoxolone methyl increased mitochondrial protein aggregation and cell death in AML lines and primary AML with high LONP1 but not hematopoietic cells or primary AML with low LONP1. In primary AML, sensitivity to LONP1 chemical inhibition or genetic depletion positively correlated with LONP1 expression (Omaveloxolone (n=16, R2=0.64); Bardoxolone methyl (n=30, R2=0.65); LONP1 shRNA (n=9, R2=71)). In summary, AML cells have increased mitochondrial protein import, necessitating a heightened dependence on the UPRmt to maintain mitochondrial proteostasis. Targeting the UPRmt at the level of LONP1 selectively induces mitochondrial protein aggregation and eliminates AML cells while sparing normal hematopoietic cells. Citation Format: Matthew Tcheng, Veronique Voisin, Marcela Gronda, Rose Hurren, Lan Xin Zhang, Yue Feng, Zaynab Mamai, Brady Stock, Yulia Jitkova, Andrea Arruda, Steven M. Kornblau, Mark D. Minden, Aaron D. Schimmer. Increased mitochondrial protein import necessitates greater reliance on the mitochondrial unfolded protein response (UPRmt) and the protease LONP1 to maintain mitochondrial protein solubility and cell viability in acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3033.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".