bims-mibica 2026-10-11 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–10–11
fifteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Respiration-Deficient Cells Require Pyruvate Carboxylase to Suppress Asparagine Auxotrophy.
Myeloid differentiation-associated autophagy drives venetoclax resistance in AML.
Pharmacological Myristoylation Inhibition by Zelenirstat Disrupts Growth Signalling, Energy Metabolism, and Migration in Triple-Negative Breast Cancer Cells.
Reactive oxygen species define leukemia stem cell identity in pediatric acute myeloid leukemia.
Inheritance and selection of the mitochondrial genome.
Djp1 is a multifunctional Hsp40 cochaperone for mitochondrial phospholipid metabolism.
Mitochondria transfer via tunneling nanotubes drives macrophage immunosuppression and metabolic reprogramming in pediatric AML.
Deoxysphingolipids activate cGAS-STING and enhance antitumor immunity.
Small molecules rescue pathogenic POLGA aggregation and restore its functions in a mouse model of PEO.
Multicancer analysis reveals mtDNA copy number as a key determinant of mutational load and cancer progression.
USF1 promotes growth and glycolysis in acute myeloid leukemia cells.
Hepatocyte Serine Palmitoyltransferase 3 is essential for mitochondrial ceramide homeostasis and electron transport chain function.
Selective elimination of quiescent cancer cells by dequalinium chloride via ROS-mediated ferroptosis.
TR-107, a novel mitochondrial ClpP agonist, induces robust antitumor activity against preclinical models of adrenocortical carcinoma.
2-Hydroxyglutarate Redirects Fatty Acid Partitioning to Mitigate Lipotoxic Stress and Preserve Metabolic Fuel.

bioRxiv. 2026 Aug 13. pii: 2026.08.12.744280. [Epub ahead of print]

Respiration-Deficient Cells Require Pyruvate Carboxylase to Suppress Asparagine Auxotrophy.

Ruobing Cui, Keun Woo Ryu, Yi Fu, Ziad Bakouny, Dayi Li, Tamar Kavlashvili, Agnel Sfeir, Craig B Thompson.

Mutations in mitochondrial DNA (mtDNA) compromise ETC activity and impair oxidative phosphorylation. Since eukaryotic cells contain multiple copies of mtDNA, the resulting phenotype depends on the proportion of mutant mitochondrial genomes (the heteroplasmy level). Using isogenic cell lines carrying similar mtDNA deletions, a linear decline in cellular respiration was observed as mitochondrial DNA heteroplasmy increased. Despite this, cellular redox imbalance did not change until heteroplasmy exceeded 50%. As heteroplasmy increased past 70%, cells also exhibited an integrated stress response (ISR) and impaired translation was observed. These defects were reversed by either addition of asparagine or overexpression of pyruvate carboxylase (PC). The dependence on exogenous asparagine in other respiration-deficient cells was found to correlate inversely with the PC expression level. For example, patient-derived thyroid tumor cells, harboring high heteroplasmy for a Complex I mtDNA mutation and low levels of PC, exhibited asparagine auxotrophy, and L-asparaginase treatment suppressed tumor growth. Together, these findings demonstrate a role for mitochondrial pyruvate carboxylase in cellular asparagine synthesis under conditions of compromised respiratory activity.

DOI: https://doi.org/10.64898/2026.08.12.744280
Res Sq. 2026 Aug 10. pii: rs.3.rs-10617934. [Epub ahead of print]

Myeloid differentiation-associated autophagy drives venetoclax resistance in AML.

James DeGregori, Johannes Menzel, Mark Gregory, Daniela Ortiz Chavez, Jacqueline Thorburn, Marco De Dominici, Daniel Pollyea, Craig Jordan, Andrew Thorburn.

Acute myeloid leukemia (AML) is a complex disease that often displays phenotypic and genotypic heterogeneity, where subclones are either refractory or frequently become resistant to treatment. Several studies have shown that the developmental stage of leukemia correlates with the response to therapies combining the BCL2 inhibitor venetoclax (Ven) with hypomethylating agents, such as azacitidine (Aza), where phenotypically primitive AML cells are sensitive and monocytic cells are more resistant. Here we show that resistant monocytic subclones have higher autophagic flux compared to sensitive primitive subclones in AMLs of mixed phenotype. Induction of AML myeloid differentiation with inecalcitol, a potent vitamin D3 analogue and vitamin D receptor (VDR) agonist, increases autophagic flux and Ven/Aza resistance. Pharmacological inhibition or genetic perturbation of autophagy negates differentiation-induced Ven/Aza resistance. We show that this myeloid differentiation-associated autophagy increases mitochondrial reserve capacity and metabolic flexibility. This work shows that autophagy-dependent metabolic rewiring during AML differentiation contributes to Ven/Aza therapy resistance.

DOI: https://doi.org/10.21203/rs.3.rs-10617934/v1
Breast Cancer (Dove Med Press). 2026 ;18 619042

Pharmacological Myristoylation Inhibition by Zelenirstat Disrupts Growth Signalling, Energy Metabolism, and Migration in Triple-Negative Breast Cancer Cells.

Rony Pain, Erwan Beauchamp, Shawn Duckett, Morris A Kostiuk, Claudia Y Acevedo-Morantes, Heather Mast, Helene Lemieux, Luc G Berthiaume.

   Background: Metastatic breast cancer cells rely on oxidative phosphorylation (OXPHOS) for energy production, yet selectively targeting mitochondrial metabolism in cancer cells remains a major therapeutic challenge. Myristoylation, the modification of proteins with the 14-carbon fatty acid myristate by N-myristoyltransferases NMT1 and NMT2, dually impacts cancer cell signalling and metabolism. The pan-NMT inhibitor zelenirstat selectively inhibits these enzymes to prevent the myristoylation of target proteins.
Methods: We assessed the effects of zelenirstat on the protein levels and metabolic activity of multiple triple-negative breast cancer (TNBC) cell lines. NDUFAF4 knockout (KO) MDA-MB-231 cells were engineered using CRISPR/Cas9. Functional assays included multiple types of respirometry, cell migration measurements, and spheroid formation.
Results: Zelenirstat treatment depleted myristoylated complex I assembly factor NDUFAF4 levels in four different TNBC cell lines. This loss effectively abrogated mitochondrial OXPHOS through impairment of complex I, resulting in reduced cellular energy production. Zelenirstat treatment resulted in NADH accumulation, loss of AMPK, and decreased glycolysis. Given that zelenirstat impacted cell signalling and OXPHOS, we further demonstrated that it also significantly impaired migration and invasion. Importantly, both zelenirstat treatment and NDUFAF4 KO TNBC MDA-MB-231 cells dramatically reduced mammosphere formation, indicating potent activity against breast cancer stem cells (BCSCs).
Conclusion: In addition to the previously shown inhibitory effect of zelenirstat on TNBC cell growth in vitro and in vivo, our new data demonstrate the widespread effects of zelenirstat on both aggressive TNBC cells and BCSCs. These findings highlight the potential of zelenirstat as an anti-metastatic agent, warranting further clinical trial evaluation in patients with TNBC.

Keywords:  OXPHOS; TNBC; cancer metabolism; cancer stem cells; myristoylation; zelenirstat

DOI:  https://doi.org/10.2147/BCTT.S619042
Cancer Lett. 2026 Oct 04. pii: S0304-3835(26)00630-0. [Epub ahead of print] 218866

Reactive oxygen species define leukemia stem cell identity in pediatric acute myeloid leukemia.

Maddalena Benetton, Ambra Da Ros, Alberto Peloso, Giorgia Longo, Sara Perpinello, Chiara Frasson, Tiago Branco Fonseca, Elena Varotto, Silvia Bresolin, Claudia Tregnago, Luca Scorrano, Benjamin J Huang, Soheil Meshinchi, Franco Locatelli, Martina Pigazzi.

  Standard chemotherapy effectively induces complete remission in most children with acute myeloid leukemia (AML), however relapse remains the main cause of treatment failure. Leukemia stem cells (LSCs) are proposed to constitute a therapy-resistant reservoir driving disease recurrence, but their reliable identification remains unresolved. We explored intracellular reactive oxygen species (ROS) levels in pediatric AML at diagnosis and sorted ROS-low (RL) and ROS-high (RH) cell fractions. We found that RL cells exhibited increased quiescence, sustained serial colony-forming capacity and engraftment in mice when compared to the RH fraction. Moreover, in a 3D niche model, RL cells preferentially localized to hypoxic regions and were resistant to cytarabine, altogether indicating enrichment for functional LSCs. Transcriptomic analyses revealed enrichment of stemness, adhesion and niche-interaction programs in RL cells, alongside downregulation of mitochondrial and oxidative phosphorylation pathways. Consistently, RL cells displayed reduced oxygen consumption and ATP production, together with remodeled cristae structure despite preserved mitochondrial mass. Paradoxically, complex I inhibition selectively impaired RL cell viability, indicating a dependency on oxidative phosphorylation. Using RL transcriptome, we derived a gene signature that, when applied to single-cell RNA-sequencing data of pediatric AML cases, identified LSCs within the bulk regardless of differentiation status, and showed significant prognostic value. Finally, transcriptional program trajectory indicated that RL fraction contributed to generate the whole AML bulk, whereas gene mutations were maintained in RL and RH cells. Overall, this ROS-based strategy represents a new tool to isolate stem cells transcending traditional markers, and identifies novel clinically relevant vulnerabilities to target LSCs.

Keywords:  cell adhesion; gene signatures; leukemia stem cells; mitochondria; pediatric acute myeloid leukemia; reactive oxygen species; transcriptomics

DOI:  https://doi.org/10.1016/j.canlet.2026.218866
Nat Rev Genet. 2026 Oct 05.

Inheritance and selection of the mitochondrial genome.

Qin Xie, Harry E Walker, Michal Minczuk, Marcos R Chiaratti, Patrick F Chinnery.

The functioning mitochondrial genome is essential for cellular energy production. Being strictly maternally inherited and possessing limited DNA repair capacity, mitochondrial DNA (mtDNA) replication errors tend to accumulate over time. If left unchecked, these errors can accumulate through the female germline over successive generations, potentially leading to species extinction. However, this outcome is not observed in most species, including humans, which implies the existence of mechanisms that counteract the progressive accumulation of deleterious mtDNA mutations. Recent technological advances are building a deeper understanding of the processes that preserve mtDNA integrity, including the molecular and cellular basis and timing of purifying selection. This new knowledge helps to explain how mtDNA can change rapidly over just a few generations, whilst remaining compatible with the independently inherited, evolving nuclear genome.

DOI: https://doi.org/10.1038/s41576-026-01019-0
bioRxiv. 2026 Aug 11. pii: 2026.08.10.743968. [Epub ahead of print]

Djp1 is a multifunctional Hsp40 cochaperone for mitochondrial phospholipid metabolism.

Rashima Prem, Alex Maya-Romero, Chi Xie, Zach Irwin, Bradley Wagaman, Pingdewinde N Sam, Salloni Gill, Ketaki Nirbhavane, Mackenzie T Primrose, Kevin Whited, Steven M Claypool.

Mitochondria are cellular energy hubs best known for ATP production via oxidative phosphorylation; however, they also serve as biosynthetic centers for phospholipids. Mitochondrial phospholipids are critical for various cellular processes, and their loss underlies myriad mitochondrial diseases. The critical enzymes underlying these biosynthetic cascades are encoded in the nucleus, translated in the cytosol, and imported into mitochondria. Understanding of mechanisms and factors that ensure precise targeting of proteins to mitochondria has been long overlooked but remains critical. Recently, the J-protein/Hsp40 cochaperone Djp1 has emerged as a key player in mitochondrial protein targeting by promoting the transfer of precursors from the endoplasmic reticulum (ER) surface to mitochondria in a pathway termed ER-SURF. Molecular details regarding how Djp1 recognizes clients and more broadly supports mitochondrial function remain unknown. Using biochemical approaches, proteomics, and thin layer chromatography, we demonstrate that Djp1 is a regulator of Phosphatidylserine decarboxylase 1 (Psd1), an inner mitochondrial membrane resident responsible for mitochondrial phosphatidylethanolamine (PE) production. This regulation of Psd1 biogenesis is dependent on its mitochondrial targeting signal and is specific to Djp1 compared to other members of the Hsp40 family or ER targeting factors. Intriguingly, the combined loss of Djp1 and Psd1 results in a synthetic sick phenotype that unexpectedly reflects a role(s) for Djp1 in proper mitochondrial phospholipid metabolism independent of Psd1. Taken together, these findings expand our understanding of Djp1-dependent mitochondrial protein regulation and unveil Djp1 as important for mitochondrial phospholipid metabolism by multiple mechanisms.

DOI: https://doi.org/10.64898/2026.08.10.743968
Leukemia. 2026 Oct 09.

Mitochondria transfer via tunneling nanotubes drives macrophage immunosuppression and metabolic reprogramming in pediatric AML.

Alicia Perzolli, Farah Massaoudi, Anita T van Oort, Joost B Koedijk, Elizabeth K Schweighart, Lennart A Kester, Fabienne Adriaanse, Kimberly Smit, Wilbert P Vermeij, Bianca F Goemans, Josef Vormoor, C Michel Zwaan, Olaf Heidenreich.

Although immunotherapy has revolutionized cancer treatment, its benefits in pediatric acute myeloid leukemia (AML) remain limited, partly due to an incomplete understanding of the AML microenvironment. While most studies focus on T cells, innate immune populations such as macrophages are less well explored. In pediatric AML patients, we demonstrate that immunosuppressive macrophages dominate the AML microenvironment and support growth of RUNX1::RUNX1T1 and KMT2A-rearranged leukemic blasts. In co-culture experiments, AML cells reprogrammed naïve and pro-inflammatory macrophages toward an anti-inflammatory state, characterized by suppression of NF-κB and other inflammatory pathways. This phenotypic switch requires direct cell contact and involves tunneling nanotube-mediated transfer of AML mitochondria to macrophages associated with metabolic rewiring toward oxidative phosphorylation. Functionally, these reprogrammed macrophages exhibited impaired phagocytosis, convey chemoresistance and reduced T cell- and bispecific antibody-mediated killing, facilitating immune escape. Our findings reveal a novel mechanism of immune suppression and suggest that targeting AML-macrophage interactions could enhance the efficacy of T cell-based immunotherapies.

DOI: https://doi.org/10.1038/s41375-026-03164-1
Cell Rep. 2026 Oct 06. pii: S2211-1247(26)01168-X. [Epub ahead of print]45(10): 118089

Deoxysphingolipids activate cGAS-STING and enhance antitumor immunity.

Suchandrima Saha, Fabiola N Velazquez, Fatemeh Dehpanah, Brianna L Bergfalk, Samantha Mulkeen, Karissa J Lopez, Cungui Mao, David C Montrose.

  Deoxysphingolipids (deoxySLs) are a class of non-canonical sphingolipids that can adversely impact mitochondrial function. Mitochondrial DNA release resulting from mitochondrial disruption can activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, and in turn, promote antitumor immunity. Here, we investigated whether inducing deoxySL accumulation in colon cancer cells drives immune-specific, antitumor effects. We show that depleting serine increased deoxySLs and enhanced immune cell infiltration in colon tumors, in parallel with suppressing tumor growth. Elevating tumor deoxySL levels in mice through mutation of serine palmitoyltransferase and feeding a high alanine diet exerted similar effects, including immune-mediated tumor growth suppression. Work conducted in multiple in vitro systems identified deoxySLs as key triggers of cGAS-STING activation, an effect mediated by the release of mitochondrial DNA under mitochondrial stress. Collectively, these findings demonstrate that deoxySLs drive antitumor immunity and identify a previously unrecognized metabolic strategy for cancer therapy.

Keywords:  CP: cancer; CP: metabolism; amino acids; chemokines; colorectal cancer; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2026.118089
EMBO Mol Med. 2026 Oct 06.

Small molecules rescue pathogenic POLGA aggregation and restore its functions in a mouse model of PEO.

Aftab Mohammed, Tavleen Kaur, Priyanka Panwar, Samanwita Ghosh, Hanif Ahmad, Sadananda Kumbhakar, Meltem Muftuoglu, Carlo Viscomi, Sagar Sengupta.

POLGA, the catalytic subunit of the mitochondrial DNA polymerase, is essential for mitochondrial DNA (mtDNA) replication and maintenance. Mutations in POLGA cause progressive external ophthalmoplegia (PEO), but the underlying pathogenic mechanisms remain unclear. Here, we show that the mitochondrial E3 ligase MITOL hyperubiquitylates PEO-associated POLGA mutants at lysine 1060, triggering conformational changes and formation of insoluble aggregates that impair their mitochondrial import and consequently compromise mtDNA replication and mitochondrial homeostasis. To identify compounds that disrupt POLGA aggregates and restore mutant POLGA function, we screened an FDA/EMA/PMDA-approved drug library using a split-GFP system. We identified two clinically approved compounds, diltiazem hydrochloride (C1) and sulbactam (C4), that disrupted POLGA aggregates, prevented aberrant MITOL recognition, restored mitochondrial import, and rescued mtDNA replication and mitochondrial function. Importantly, treatment with either compound significantly improved motor performance in a knock-in mouse model carrying the disease-relevant A467T-equivalent POLGA mutation. These findings establish pathogenic aggregation as a previously underrecognized disease mechanism and demonstrate that disrupting POLGA aggregates with repurposed drugs can restore mitochondrial function in vivo, providing a potential therapeutic strategy for POLGA-associated mitochondrial disease.

DOI: https://doi.org/10.1038/s44321-026-00532-3
FEBS J. 2026 Oct 07.

Multicancer analysis reveals mtDNA copy number as a key determinant of mutational load and cancer progression.

Anamika Acharyya, Riddhiman Dhar.

  Mitochondrial DNA (mtDNA) copy number determines the functional state of mitochondria and thus, influences cellular energy production, growth, metabolism, and stress response. Variation in mtDNA copy number has been observed across many cancer types and has been linked to changes in gene expression. However, whether mtDNA copy number has any link to mutation accumulation in cancer is unknown. Further, how mtDNA copy number variation alters expression of cancer-associated pathways and thereby influences cancer progression remains unclear. Here, through an analysis of whole genome data in multiple cancer types, we show that mtDNA copy number increases with an increase in mutational load in cancer samples and the increase in mtDNA copy number bears a signature of compensation for mitochondrial function. We also show that the samples with low-mtDNA generally have increased expression of cancer-promoting genes, including genes involved in cell migration and epithelial-mesenchymal transition (EMT). Taken together, these results reveal a close association of mtDNA copy number with mutational load and disease progression in cancer. These findings provide a way forward toward a better understanding of the role of mtDNA copy number and mitochondrial functional state in cancer progression.

Keywords:  MtDNA copy number; cancer progression; differential expression; epithelial–mesenchymal transition; multicancer analysis; mutational load

DOI:  https://doi.org/10.1111/febs.70736
Biochim Biophys Acta Mol Basis Dis. 2026 Oct 06. pii: S0925-4439(26)00363-7. [Epub ahead of print] 168497

USF1 promotes growth and glycolysis in acute myeloid leukemia cells.

Nianxue Wang, Yunshuang Guan, Ruya Zhang, Can Yang, Liping Shu, Xijun Wu.

  Acute myeloid leukemia (AML) is a hematological malignancy characterized by impaired hematopoiesis and aggressive progression, with limited treatment options and poor prognosis, especially in elderly patients. Metabolic reprogramming, particularly enhanced glycolysis, is a hallmark of AML and contributes to disease progression and therapy resistance. Upstream stimulatory factor 1 (USF1) regulates metabolism, the cell cycle, and oncogenesis in solid tumors, whereas its role in AML remains unclear. Herein, we investigated the role and underlying mechanism of USF1 in regulating USP25 transcription and promoting AML progression. We found that USF1 was highly expressed in AML samples and cell lines, and its elevated expression was associated with poor prognosis. Functional assays showed that USF1 promoted AML cell growth and glycolysis while inhibiting apoptosis. Mechanistically, USF1 directly bound to the USP25 promoter, enhancing its transcription. Knockdown of USP25 reversed the tumor-promoting effects of USF1. Moreover, in vivo studies demonstrated that silencing USF1 significantly inhibited tumor growth. In conclusion, USF1 promotes AML cell growth and glycolysis through the transcriptional activation of USP25, thereby identifying the USF1-USP25 axis as a potential therapeutic target for AML.

Keywords:  Acute myeloid leukemia; Glycolysis; Transcriptional regulation; USF1; USP25

DOI:  https://doi.org/10.1016/j.bbadis.2026.168497
J Biol Chem. 2026 Oct 09. pii: S0021-9258(26)02502-0. [Epub ahead of print] 113630

Hepatocyte Serine Palmitoyltransferase 3 is essential for mitochondrial ceramide homeostasis and electron transport chain function.

Maryam Jamil, Anna Kovilakath, Yolander Valentine, Saaid Farooq, David Montefusco, Yang Yue, Gisela Beutner, Qun Chen, Jeremy Thompson, Komuraiah Myakala, Xiaoxin Wang, Christiane Carter, Jinze Liu, Arjun Rijal, Charles E Lyons, Devanand Sarkar, Moshe Levi, George A Porter, Sushil Mahata, Tytus Bernas, Edward J Lesnefsky, L Ashley Cowart.

  Sphingolipids constitute essential membrane lipids that also function as signaling molecules mediating fundamental cellular processes. Disruption of constitutive sphingolipid metabolism contributes to a range of metabolic diseases. Sphingolipid biosynthesis is initiated by serine palmitoyltransferase (SPT), a heteromeric enzyme composed of Sptlc1 and either Sptlc2 or the less-characterized subunit Sptlc3. While the canonical Sptlc1/Sptlc2 complex generates most sphingolipids, Sptlc1/Sptlc3 produces non-canonical sphingolipids that remain poorly understood. Sptlc3 expression increases in liver disease in both mouse models and humans, yet its biological role remains unclear. To address this, we generated a liver-specific SPTLC3 knockout (SPT3-hKO) mouse model. Loss of SPTLC3 resulted in severe mitochondrial dysfunction in hepatocytes, characterized by reduced oxygen consumption, decreased ATP production, and elevated NADH/NAD+ ratios with a concomitant increase in glycolytic activity. Mechanistically, we found a defect in the electron transport chain (ETC) which stemmed not from intrinsic impairment of the ETC complexes but rather from hindered electron flow between complex I and complex III likely due to reduced availability of Coenzyme Q. While atypical ceramides constituted (∼4% of total ceramides) when measured in liver homogenates, there measurements in mitochondria-enriched fractions revealed enrichment in this cell compartment. Together, our findings identify SPTLC3 as a critical modulator of mitochondrial ceramide composition and ETC function, revealing a specialized role for non-canonical sphingolipids in hepatocyte energy metabolism.

Keywords:  Ceramides; Complex I; ETC; Hepatocytes; SPTLC3

DOI:  https://doi.org/10.1016/j.jbc.2026.113630
FEBS Open Bio. 2026 Oct 05.

Selective elimination of quiescent cancer cells by dequalinium chloride via ROS-mediated ferroptosis.

Kotaro Miyamoto, Shiori Sakai, Minori Endo, Terigele, Mizuho Niibori, Taiki Morita, Yu Goto, Arisa Yoshida, Tomohiro Tanaka, Ning Lin, Takahiro Kuchimaru, Hiroyuki Nakamura, Masahiro Inoue, Shinae Kizaka-Kondoh, Tetsuya Kadonosono.

  Quiescent cancer cells (QCCs) drive tumor dormancy and recurrence through their resistance to conventional therapies. Furthermore, because QCCs rely on oxidative phosphorylation and maintain a fragile redox balance, we hypothesized that they harbor a targetable redox vulnerability. Here, we show that the mitochondria-targeted agent dequalinium chloride (DQ) selectively kills QCCs in hypoxia- and nutrient limitation-induced quiescent models, including H2228 cells, multicellular spheroids, and colorectal cancer organoids, while sparing proliferating cells and normal fibroblasts. DQ induces ROS accumulation beyond the survival threshold of QCCs, leading to lipid peroxidation and ferroptotic cell death, whereas proliferating cells undergo limited caspase-independent apoptosis. These findings highlight redox imbalance as an actionable vulnerability of QCCs and position DQ as a potential repurposed agent for eliminating QCCs.

Keywords:  dequalinium chloride; ferroptosis; mitochondria; quiescent cancer cells; reactive oxygen species

DOI:  https://doi.org/10.1002/2211-5463.70344
bioRxiv. 2026 Aug 11. pii: 2026.08.10.743339. [Epub ahead of print]

TR-107, a novel mitochondrial ClpP agonist, induces robust antitumor activity against preclinical models of adrenocortical carcinoma.

George I Karadimov, Yoo Sun Kim, Haiqing Fu, Sidhant Narula, Fathi Elloumi, Anjali Dhall, Frank Echtenkamp, Luowei Li, Edwin J Iwanowicz, Lee M Graves, King Chan, Thorkell Andresson, Robert W Robey, Yoshimi Greer, Stanley Lipkowitz, Chuong D Hoang, Jonathan M Hernandez, Yves Pommier, Mirit I Aladjem, Urbain Weyemi, Myriem Boufraqech, Suresh M Kumar, Jaydira Del Rivero.

Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy originating from the adrenal cortex with limited effective treatment options. The underlying pathophysiology of ACC is uniquely characterized by abnormal steroid production and increased metabolic activity, highlighting the critical role of mitochondria in adrenal steroid hormone biosynthesis and tumor metabolism. In this study, we investigated the therapeutic potential of TR-107, a novel and highly selective small-molecule agonist targeting the mitochondrial protease ClpP. Pharmacologic hyperactivation of ClpP disrupts mitochondrial proteostasis and bioenergetics and has shown promising antitumor activity in various preclinical models. Our results demonstrated that TR-107 induces potent dose-dependent cytotoxic effects at nanomolar concentrations in ACC cell lines NCI-H295R and mACC3 as well as short-term ACC patient-derived organoid (PDO) models, markedly reducing cell viability and confluency in vitro . Metabolic analyses revealed that TR-107 significantly impaired oxygen consumption, indicating a disruption of oxidative phosphorylation and substantial attenuation of basal cellular respiration. Mechanistic studies showed dose-dependent increases in reactive oxygen species (ROS) levels and upregulation of proteins involved in mediating the ferroptotic rheostat. Pharmacokinetic assessment uncovered that TR-107 was not a substrate of the ABCB1 (MDR1/P-glycoprotein) efflux transporter, suggesting potential to overcome common multidrug resistance mechanisms. Given the importance of IGF-2 signaling in ACC, we further explored the combinatorial effects of TR-107 with IGF-1 receptor (IGF-1R) inhibitors and discovered that co-treatment produced synergistic reductions in cell viability across NCI-H295R, mACC3, and ACC PDOs. Collectively, these findings support the potential of mitochondrial ClpP hyperactivation as a promising therapeutic strategy for ACC and demonstrate that TR-107 exhibits significant antitumor activity as a monotherapy or in combination with IGF-1R inhibitors. These findings provide a strong rationale for advancing ClpP agonists into clinical development for the management of ACC.

DOI: https://doi.org/10.64898/2026.08.10.743339
bioRxiv. 2026 Aug 13. pii: 2026.08.12.744465. [Epub ahead of print]

2-Hydroxyglutarate Redirects Fatty Acid Partitioning to Mitigate Lipotoxic Stress and Preserve Metabolic Fuel.

Niv Vigder, Amit Chandra, Nishith Shrimali, Sergey Tumanov, Vlad Elgart, Huamei He, Ryan Mulhern, Ram P Chakrabarty, Navdeep S Chandel, Stuart Cordwell, Steven P Gygi, João A Paulo, Joseph Loscalzo.

The role of 2-hydroxyglutarate in lipid metabolism is currently unknown. Here we show that 2HG redistributes the partitioning of fatty acids into triglyceride storage and away from membrane phospholipid synthesis, mitochondrial oxidation, and lipotoxic intermediates. In primary human cardiac and vascular cells, both enantiomers, D2HG and L2HG, expanded triglyceride stores and lipid droplets while selectively depleting phosphatidylethanolamine, with L2HG acting more potently than D2HG despite lower intracellular accumulation. Mechanistically, L2HG increases DGAT-dependent triglyceride synthesis, slows triglyceride turnover, and constrains the ethanolamine branch of the Kennedy pathway. This response limits fatty acid oxidation, long-chain acylcarnitine accumulation, and lipid peroxidation independently of pseudohypoxic transcription or canonical lipid storage regulators, while also remodeling the phosphoproteome and redox proteome. L2HG accumulation induces hypertriglyceridemia in mice, redistributes the acyl chain composition of cardiac triglycerides, and limits ischemia-induced acylcarnitine accumulation in the heart, mirroring a positive association between circulating 2HG and triglycerides in humans. Thus, 2HG expands metabolic flexibility from whether fatty acids are used as fuel to how that fuel is allocated among storage, membrane synthesis, and oxidation.

DOI: https://doi.org/10.64898/2026.08.12.744465