bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–06–21
eight papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.
  2. Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
  3. Targeting mitochondrial TRIP13-AIF interaction suppresses myeloid leukemia progression and overcomes drug resistance.
  4. SLC25A3 exports mitochondrial copper to metalate cytochrome c oxidase and prevent cuproptosis.
  5. Venetoclax and hypomethylating agents synergize to increase cell death and metabolic remodeling in acute B-lymphoblastic leukemia cells.
  6. Targeting STAT3-mediated lipid metabolism reprogramming overcomes chemoresistance in acute myeloid leukemia.
  7. ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.
  8. Electron transport chain activity balances cell cycle progression and differentiation of retinal progenitor cells.
  1. EMBO Mol Med. 2026 Jun 17.
    Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.
    Aniketh Bishnu, Juan Zapata-Muñoz, Robert W Taylor, Kei Sakamoto, Ian G Ganley.
      Distinct mitophagy pathways can eliminate not only damaged mitochondria but also healthy ones. In Mitochondrial DNA Depletion Syndrome 13 (MTDPS13), dysregulated BNIP3/NIX-driven mitophagy of functional mitochondria is thought to be the key pathological driver. Patient mutations in the E3 ubiquitin ligase FBXL4 impair the proteasomal degradation of the mitophagy receptors BNIP3 and NIX, causing their accumulation and excessive mitophagy. As a result, mitochondrial content and oxidative phosphorylation decline sharply across multiple tissues, leading to early mortality, with no effective treatments currently existing. Here, we build on our work showing that AMPK can inhibit mitophagy via sequestration of the ULK1 autophagy-initiating kinase ULK1 and demonstrate that it is also critically relevant for mitophagy induced by FBXL4 disruption. Using FBXL4-deficient cells, as well as fibroblasts derived from MTDPS13 patients and a chemically-induced mouse model, we show that small molecule AMPK activation inhibits BNIP3/NIX-mediated mitophagy and recovers functional mitochondrial content. This work therefore validates AMPK as a realistic target in treating MTDPS13.
    DOI:  https://doi.org/10.1038/s44321-026-00471-z
  2. J Clin Invest. 2026 Jun 16. pii: e196687. [Epub ahead of print]
    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.
      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 (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. 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 UPRmt protease LONP1 in buffering stress from mitochondrial protein import in AML.
    Keywords:  Cancer; Cell biology; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI196687
  3. Oncogene. 2026 Jun 13.
    Targeting mitochondrial TRIP13-AIF interaction suppresses myeloid leukemia progression and overcomes drug resistance.
    Yao Zhu, Hongcai Liu, Fuqiang Wang, Minjie Li, Nana Wang, Shuyue Zhan, Wenjie Sun, Shengxi Li, Xun Wang, Lin Wang, Lianjun Zhang, Zhimin Gu.
      Venetoclax-based therapies have revolutionized acute myeloid leukemia (AML) treatment, yet disease progression remains a challenge due to limited response and acquired drug resistance. Identifying molecular drivers of AML progression and resistance is essential for improving therapeutic outcomes. Genes normally silenced in normal tissues but aberrantly activated in cancers, such as Cancer-Testis (CT) genes, are promising targets for cancer diagnostics and therapy. Through a CRISPR screen focused on CT genes and cancer-associated genes exhibiting a CT-like expression profile (CT-like gene), we identified the ATPase TRIP13 as critical for AML progression while dispensable for normal hematopoiesis in genetic mouse models. Mechanistically, we discovered that TRIP13 localizes to mitochondria, where it interacts with apoptosis-inducing factor (AIF), a component of respiratory complex I. This interaction promotes leukemia progression and confers drug resistance by preventing AIF translocation to the nucleus, thereby reducing apoptotic priming and shifting energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS) coupled with increased fatty acid oxidation (FAO). Genetic or pharmacological disruption of the TRIP13-AIF interaction suppressed OXPHOS, reduced leukemia cell viability, and overcame venetoclax resistance in vitro and in vivo. These findings uncover a novel mechanism by which AML cells exploit germline programs to sustain progression and resist therapy, positioning the TRIP13-AIF interaction as a promising therapeutic target for AML.
    DOI:  https://doi.org/10.1038/s41388-026-03852-3
  4. Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2612098123
    SLC25A3 exports mitochondrial copper to metalate cytochrome c oxidase and prevent cuproptosis.
    Mohammad Zulkifli, Ifrah Farid, Laura E Oldfather, Vinit C Shanbhag, Scot C Leary, Michael J Petris, Paul A Cobine, Vishal M Gohil.
      Copper (Cu) is an essential cofactor for cytochrome c oxidase (CcO), a mitochondrial respiratory chain enzyme that is metalated in the intermembrane space (IMS) primarily using Cu derived from the mitochondrial matrix pool. While Cu import into the matrix depends on the inner membrane carrier SLC25A3, the route by which matrix Cu is exported to the IMS for insertion into CcO has remained a major, unresolved step in intramitochondrial Cu trafficking. Here, we leveraged our recent discovery that the Cu ionophore elesclomol (ES) releases Cu directly into the mitochondrial matrix to show that SLC25A3 is required for exporting Cu to the IMS for CcO metalation. Loss of SLC25A3 decreases mitochondrial Cu content and CcO activity as expected. Strikingly, bypassing the loss of SLC25A3 with ES-mediated Cu delivery to the matrix fails to restore CcO function; rather, it drives toxic Cu retention and triggers cuproptosis, revealing that SLC25A3-facilitated Cu export is the limiting determinant of CcO metalation. Heterologous expression in Lactococcus lactis confirms that SLC25A3 can mediate Cu export. These results suggest that SLC25A3 is the long-sought mitochondrial Cu exporter with a dual role in enabling CcO metalation and gating susceptibility to cuproptosis.
    Keywords:  SLC25A3; copper; cuproptosis; cytochrome c oxidase; elesclomol
    DOI:  https://doi.org/10.1073/pnas.2612098123
  5. Mol Metab. 2026 Jun 17. pii: S2212-8778(26)00086-4. [Epub ahead of print] 102402
    Venetoclax and hypomethylating agents synergize to increase cell death and metabolic remodeling in acute B-lymphoblastic leukemia cells.
    Patricia Maass, Sandra Lange, Felix Wittig, Nares Trakooljul, Frieder Hadlich, Anett Sekora, Christian Schmidt, Hugo Murua Escobar, Klaus Wimmers, Burkhard Hinz, Christian Junghanss, Anna Richter.
      Overexpression of anti-apoptotic protein BCL-2 and hypermethylation are hallmarks of acute lymphoblastic leukemia (ALL) and can be pharmacologically addressed by venetoclax (VEN) and hypomethylating agents (HMA) such as azacytidine (AZA) or decitabine (DEC). Combined VEN and HMA application was recently successfully implemented into the clinical treatment regimen of acute myeloid leukemia but has so far not been investigated in ALL. We therefore analyzed the anti-leukemic potential of VEN+HMA in four ALL cell lines and identified potential modes of synergy to overcome mono-drug-induced resistance. All substances influenced cell proliferation and induced apoptosis in a subset of the tested cell lines. Investigating potential ways of synergy, combined VEN and HMA application resulted in significantly reduced metabolic activity in all investigated cell lines. In contrast, no synergistic effects were observed regarding the BCL-2 protein and methyltransferase expression or global methylation. Single cell RNAseq of a patient-derived xenograft model revealed that VEN interferes with both main energy supply routes, oxidative phosphorylation as well as glycolysis, to impede the cells' metabolism and mitochondrial activity. The addition of HMA, especially DEC, further increased anti-metabolic effects, leading to a strong reduction of basal and maximal respiration, ATP production and proton leakage. AZA-induced metabolic suppression as well as overall anti-leukemic activity alone and in combination with VEN was generally weaker compared to DEC. Altogether, we herein demonstrate that combined VEN and HMA application acts synergistically and significantly reduces the leukemic burden in ALL cell lines via impairment of tumor cell metabolism and mitochondrial function.
    DOI:  https://doi.org/10.1016/j.molmet.2026.102402
  6. Cell Death Dis. 2026 Jun 17.
    Targeting STAT3-mediated lipid metabolism reprogramming overcomes chemoresistance in acute myeloid leukemia.
    Keren Peng, Jianshan Mo, Zhenjiao Yang, Wen Ding, Jiayu Yan, Shumin Ouyang, Minyuan Lu, Kai Zhu, Hongru Yao, Huiqin Chen, Xiongjun Xu, Peibin Yue, Jinjian Lu, Yuanxiang Wang, Shanyi Zhang, Yandong Wang, Xiaolei Zhang.
      Chemotherapy resistance and intolerance present significant challenges in the effective treatment of acute myeloid leukemia (AML). However, the role of metabolic reprogramming, particularly lipid metabolic rewiring, in promoting chemotherapy resistance in leukemia has not been fully elucidated. Here, we found that multiple lipid metabolism processes are aberrantly activated in Ara-C resistant AML cells, accompanied by upregulation of JAK-STAT3 signaling and key lipid metabolic regulators, notably SREBP1 and CPT2. Additionally, we discovered W1307, a potent and highly selective STAT3 inhibitor, which demonstrated significant anti-tumor activity both in vitro and in vivo. Genetic and pharmacological inhibition of STAT3 simultaneously suppresses lipid synthesis and catabolism, leading to lipids metabolic disorder accompanied with lipids accumulation, ROS increase, lipid peroxidation and mitochondrial membrane potential decrease. Mechanistically, STAT3 binds to DNA response elements in the promoters of the lipid metabolism associated gene SREBF1 and CPT2, and regulates their expression. Furthermore, inhibition of STAT3 enhances the anti-tumor effect of Ara-C and sensitizes resistant AML cell line to Ara-C through disrupting lipid homeostasis and triggering lipotoxicity. Our findings highlight the critical role of STAT3-driven lipid metabolism reprogramming in chemoresistance. Furthermore, W1307 emerges as a promising therapeutic candidate to overcome chemoresistance in leukemia treatment.
    DOI:  https://doi.org/10.1038/s41419-026-08988-4
  7. Nat Commun. 2026 Jun 20.
    ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.
    Jacklyn M Huhn, Liana Valin, Mary Basse, Judith Sokei, Nishanth Gabriel, Esteban Martinez, Joice S Kanefsky, Stephanie Stransky, Adrienne Dorrance, Ramiro Garzon, Daniela Di Marcantonio, Tomasz Skorski, Aaron R Goldman, Hsin-Yao Tang, Samuele Cortellazzi, Orsola di Martino, John Krais, Simone Sidoli, Francesca Ferraro, David L Wiest, Stephen M Sykes.
      Proper timing of DNA replication relies on sufficient nucleotide pools and replication machinery. The upstream regulatory programs that support the biomass production needed for DNA replication, particularly in the accelerated growth setting of cancer, remain incompletely defined. Here we show that the transcription factor ATF4 coordinates amino acid and nucleotide metabolism with selective protein synthesis to ensure proper DNA replication initiation and timing in acute leukemia. Specifically, ATF4 promotes the expression of enzymes that biosynthesize amino acids required for nucleotide production and drive the transcription of tRNA charging enzymes that sustain translation of a subset of proteins involved in replication origin firing. Consequently, ATF4 inhibition limits nucleotide biosynthesis and replication machinery, thereby disrupting DNA replication timing and leading to leukemia cell differentiation and death. Our findings indicate that ATF4 coordinates metabolic and translational programs to maintain DNA replication fidelity and the differentiation blockade in leukemia cells.
    DOI:  https://doi.org/10.1038/s41467-026-74324-1
  8. Exp Eye Res. 2026 Jun 17. pii: S0014-4835(26)00283-6. [Epub ahead of print]270 111127
    Electron transport chain activity balances cell cycle progression and differentiation of retinal progenitor cells.
    Elda M Rueda, Ella Wasel, Carlina M Schubert, Anthony P Barrasso, Xuefei Tong, Ross A Poché.
      The retina is considered one of the most metabolically active tissues in the mammalian central nervous system. Prior studies have defined the extent of metabolic diversity among all seven adult retinal cell types. However, the specific metabolic changes in retinal progenitor cells (RPCs) during development remain unknown. In this study, we characterized the histochemical patterns of oxidative phosphorylation (OXPHOS) and glycolysis indicators in the differentiating and maturing mouse retina. Also, by performing RPC-specific conditional knockout (CKO) of the mitochondrial transcription factor A (Tfam), we generated retinas in which RPC OXPHOS activity was lost throughout retinogenesis. We found that early-stage (embryonic) Tfam CKO RPCs were completely OXPHOS-deficient yet underwent normal proliferation, cell cycle exit, and differentiation into retinal neurons. In contrast, late-stage (postnatal) RPCs remained in a proliferative state well past the normal developmental period, leading to a later reduction in the generation of bipolar cells and Müller glia. Ultimately, as the CKO retina fully matures, it becomes severely hypoplastic due to cell death that we attribute to the previous loss of bipolar cells and Müller glia. In total, our data establishes that, over time, RPCs exhibit heterogeneity in their metabolic requirements, with the second wave of RPCs being more reliant on OXPHOS activity to undergo proper neurogenesis.
    Keywords:  Metabolism; Mitochondria; Oxidative phosphorylation; Retinal progenitor cells; Retinogenesis
    DOI:  https://doi.org/10.1016/j.exer.2026.111127
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