bims-mibica 2025-11-02 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–11–02
ten papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.
Metformin induces ferroptosis associated with lipidomic remodeling in AML.
VDAC1 inhibitor DIDS uncouples respiration in isolated tissue mitochondria and induces mitochondrial hyperfusion in mammalian cells.
Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.
A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.
Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.
Mitochondrial Protease ClpP: Cancer Marker and Drug Target.
Venetoclax and new BCL-2 inhibitors in acute myeloid leukemia.
Dihydroorotate dehydrogenase inhibition activates STING pathway and pyroptosis to enhance NK cell-dependent tumor immunotherapy.
The cancer-induced lactate load and oncologic remodeling hypothesis: lactate as a driver of biosynthesis and epigenetics in cancer.

Mol Cell. 2025 Oct 28. pii: S1097-2765(25)00819-6. [Epub ahead of print]

Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.

Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Niklas B Thompson, Peter A Faull, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.

  The de novo purine synthesis pathway is fundamental for nucleotide production, yet the role of mitochondrial metabolism in modulating this process remains underexplored. Here, we identify that succinate dehydrogenase (SDH) is essential for maintaining de novo purine synthesis. Genetic or pharmacological inhibition of SDH suppresses purine synthesis, contributing to a decrease in cell proliferation. Mechanistically, SDH inhibition elevates succinate, which in turn promotes the succinylation of serine hydroxymethyltransferase 2 (SHMT2) within the mitochondrial tetrahydrofolate (THF) cycle. This post-translational modification lowers formate output, depriving cells of one-carbon units needed for purine assembly. In turn, cancer cells activate the purine salvage pathway, a metabolic compensatory adaptation that represents a therapeutic vulnerability. Notably, co-inhibition of SDH and purine salvage induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings reveal a signaling role for mitochondrial succinate in tuning nucleotide metabolism and highlight a dual-targeted strategy to exploit metabolic dependencies in cancer.

Keywords:  TCA cycle; cancer; formate; mitochondrial metabolism; nucleotide metabolism; succinate

DOI:  https://doi.org/10.1016/j.molcel.2025.10.002
Blood Adv. 2025 Oct 31. pii: bloodadvances.2025016155. [Epub ahead of print]

Metformin induces ferroptosis associated with lipidomic remodeling in AML.

Dominique Sternadt, Diego A Pereira-Martins, Prodromos Chatzikyriakou, Luise Albuquerque-Simões, Ming Yang, Douglas R Silveira, Albertus Tj Wierenga, Isabel Weinhäuser, Shanna M Hogeling, Lieve Oudejans, Pilar Casares-Alaez, Jean-Emmanuel Sarry, Christian Frezza, Gerwin A Huls, Lynn Quek, Jan Jacob Schuringa.

Metabolic reprogramming is a hallmark of cancer, essential for sustaining leukemogenesis. In acute myeloid leukemia (AML), high dependency on oxidative phosphorylation (OXPHOS) is often linked to poor outcomes and inhibiting this pathway has shown to be highly effective. However, most OXPHOS inhibitors are not clinically translatable due to significant side effects. Thus, repurposing safe FDA-approved drugs that can target OXPHOS is of great interest. Here, we evaluated metformin, an antidiabetic drug that inhibits OXPHOS, in a genetically diverse panel of primary AML samples to identify metabolic profiles predicting treatment susceptibility. Using label-free quantitative proteome analysis on sorted CD34+/CD117+ AML, we performed single-sample gene set enrichment analysis focused on metabolic terms and correlated enrichment scores with metformin sensitivity, followed by functional studies. Ex vivo treatment of AML samples with metformin showed a significant increase in ROS levels and ferroptosis induction, especially in samples with disturbed lipid metabolism, such as IDH2- and FLT3-mutant AMLs. In IDH2-mutant cells, co-treatment with palmitate, a saturated fatty acid (FA), increased metformin sensitivity, which could be rescued by CD36 knockdown, rendering these cells more resistant to treatment. Lipidomic analysis revealed profound alterations upon metformin treatment, including increased production of triglycerides and polyunsaturated FAs, further supporting a metabolic shift. We observed upregulation of genes related to lipid droplet formation, including DGAT1, a key enzyme in this process. DGAT1 inhibition was strongly synergistic with metformin, while iron chelators acted antagonistically. Our results underscore the potential of leveraging metabolic vulnerabilities in AML to identify more effective and personalized therapeutic strategies.

DOI: https://doi.org/10.1182/bloodadvances.2025016155
BBA Adv. 2025 ;8 100171

VDAC1 inhibitor DIDS uncouples respiration in isolated tissue mitochondria and induces mitochondrial hyperfusion in mammalian cells.

Surajit Das, Arpita Dutta, Minakshi Bedi, Arumay Pal, Shubhra Majumder, Alok Ghosh.

  Mitochondrial outer membrane protein, voltage-dependent anion channel 1 (VDAC1), is a gatekeeper of transport, metabolism, and cellular apoptosis. Ablation of VDAC1 or treatment with small molecular VDAC1 inhibitors often causes metabolic reprogramming in cells. However, the mechanism of VDAC1-mediated reprogramming of mitochondrial oxidative phosphorylation (OXPHOS) is still unclear. To address this problem, we tested how the high-affinity VDAC1 inhibitor, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), changes cell viability and mitochondrial functions. The IC50 value of DIDS was found 508 µM and 580 µM after 24 h of treatment on human osteosarcoma U2OS and mouse NIH-3T3 fibroblast cells. Moreover, when we inhibited mitochondrial OXPHOS by oligomycin A, 500 µM DIDS was found to uncouple the respiration like the conventional uncoupler CCCP in both the cells. Additionally, we observed that 50-200 µM DIDS, even after 2 h of treatment, depolarizes mitochondrial membrane potential. Also, brief DIDS treatment leads to an increase in cell population with hyperfused mitochondria and attenuation of DRP1 recruitment to mitochondria in U2OS cells. However, no significant alteration in the steady-state level of mitochondrial respiratory chain complex I and complex V subunits was noticed after DIDS treatment. Similar to cell lines, DIDS treatment also showed significant respiratory uncoupling in isolated mitochondria prepared from the normal muscle, liver, and sarcoma tumor tissues of mice. Finally, in silico modeling using AutoDock Vina and AlphaFold3 identified that DIDS binds inside the beta-barrel structure of VDAC1. Together, our findings directly demonstrate that DIDS binds to the VDAC1 inner pocket, uncouples OXPHOS, and promotes mitochondrial hyperfusion.

Keywords:  DIDS; Mitochondrial dynamics; OXPHOS; Uncoupling; VDAC1; mitochondria

DOI:  https://doi.org/10.1016/j.bbadva.2025.100171
Nat Commun. 2025 Oct 27. 16(1): 9481

Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.

Melina Daniilidis, Umut Günsel, Georgios Broutzakis, Kira D Leitl, Robert Janowski, Kai Fredriksson, Dierk Niessing, Christos Gatsogiannis, Franz Hagn.

The voltage-dependent anion channel (VDAC) is the main gateway for metabolites across the mitochondrial outer membrane. VDAC oligomers are connected to apoptosis induced by various stimuli. However, the mechanistic and structural basis of apoptosis induction by VDAC remains poorly understood. Here, using cryo-EM and NMR we show that VDAC1 oligomerization or confinement in small lipid nanodiscs triggers the exposure of its N-terminal α-helix (VDAC1-N) which becomes available for partner protein binding. NMR and X-ray crystallography data show that VDAC1-N forms a complex with the BH3 binding groove of the anti-apoptotic Bcl2 protein BclxL. Biochemical assays demonstrate that VDAC1-N exhibits a pro-apoptotic function by promoting pore formation of the executor Bcl2 protein Bak via neutralization of BclxL. This mechanism is reminiscent of BH3-only sensitizer Bcl2 proteins that are efficient inducers of Bax/Bak-mediated mitochondrial outer membrane permeabilization and ultimately apoptosis. The VDAC pathway most likely responds to mitochondrial stress or damage.

DOI: https://doi.org/10.1038/s41467-025-65363-1
Cell Rep. 2025 Oct 29. pii: S2211-1247(25)01267-7. [Epub ahead of print]44(11): 116496

A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.

Ting Liu, Ji-Hao Zhou, Yongbo Gong, Ying Zhang, Yongcan Ma, Xiaowen Zhang, Mohammad Minhajuddin, Wenjie Song, Zixuan Zhuang, Ana Vujovic, Youli Lu, Ang Jia, Rongqun Guo, Ruobing Ren, Lu Zhou, Yu Xiong, Linzhang Huang, Xingrong Du, Tong-Jin Zhao, Peng Li, Craig T Jordan, Haobin Ye.

  Targeting mitochondria emerges as a promising anti-leukemia strategy, yet selective mitochondrial disruption remains challenging. Here, we identified elevated mitochondrial membrane potential (MMP) as a hallmark of leukemic transformation and chemotherapy-resistant cells, prompting screening for MMP-targeting agents. Alexidine (AD), an MMP-depleting compound, demonstrated potent anti-leukemic activity with low toxicity. Mechanistically, AD binds unsaturated cardiolipin to destabilize the inner membrane localization of mitochondrial ribosome, suppressing cardiolipin-dependent mitochondrial translation, a process validated as an independent prognostic marker in leukemia. Interestingly, intercellular heterogeneity in mitochondrial translation drives heterogeneous MMP states within the population, which is associated with stemness and chemoresistance. Intriguingly, this intra-population MMP difference stems not from cardiolipin-mediated translation but from asparagine-driven mitochondrial protein synthesis-a mechanism leukemia cells selectively activate to evade chemotherapy. Critically, pharmacological asparagine depletion synergistically enhances chemosensitivity by disrupting this resistance pathway. Our findings establish that MMP regulation through cardiolipin-maintained homeostasis and asparagine-fueled adaptation represents therapeutic vulnerabilities, advocating co-targeting strategies to overcome resistance.

Keywords:  CP: cancer; alexidine; asparagine; leukemia stem cells; mitochondrial membrane potential; mitochondrial translation

DOI:  https://doi.org/10.1016/j.celrep.2025.116496
Nat Cell Biol. 2025 Oct 31.

Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.

Qiaochu Li, Konstantin Weiss, Fuateima Niwa, Jan Riemer, Thorsten Hoppe.

The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility in Caenorhabditis elegans and render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine-GCN2-SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer.

DOI: https://doi.org/10.1038/s41556-025-01799-3
Pharmaceuticals (Basel). 2025 Sep 25. pii: 1443. [Epub ahead of print]18(10):

Mitochondrial Protease ClpP: Cancer Marker and Drug Target.

Domenico Armenise, Olga Maria Baldelli, Anselma Liturri, Gianfranco Cavallaro, Cosimo Gianluca Fortuna, Savina Ferorelli, Morena Miciaccia, Maria Grazia Perrone, Antonio Scilimati.

  Background: The human mitochondrial ClpP is a serine protease located in the mitochondrial matrix responsible for degrading short lived regulatory proteins as well as misfolded or damaged proteins, thereby maintaining cellular homeostasis. Proteastasis dysregulation is linked to tumor progression. Methods: We conducted a literature review (2020-2025) using PubMed and Scopus, focusing on studies addressing ClpP structure, function, activity modulation, and cancer relevance. Keywords included "ClpP", "ClpP activators", "ClpP inhibitors", and "mitochondrial protease". Results: ClpP is upregulated in many tumors compared to normal tissues. Cancer cells depend on ClpP for mitochondrial proteostasis, metabolic adaptation, and survival. ClpP proteolytic activity modulation-via activators or inhibitors-disrupts these processes showing efficacy even in clinical setting. Conclusions: ClpP is emerging as a key player in cancer pathophysiology and holds potential as a therapeutic target. Its selective overexpression in tumors, along with its involvement in mitochondrial homeostasis, makes it a compelling candidate for precision oncology.

Keywords:  ClpP activators/inhibitors; ClpP overexpression; cancer; human ClpP protease; mitochondrial proteostasis; quality control system

DOI:  https://doi.org/10.3390/ph18101443
Expert Opin Pharmacother. 2025 Oct 27.

Venetoclax and new BCL-2 inhibitors in acute myeloid leukemia.

Pasquale Niscola, Gianfranco Catalano, Gloria Pasqualini, Daniela Piccioni, Marco Giovannini, Nelida Inés Noguera.

   INTRODUCTION: The development of B-cell lymphoma-2 (BCL-2) inhibitors has totally revolutionized the management of acute myeloid leukemia (AML). These highly effective, small molecules trigger apoptosis in leukemia cells by specifically targeting the BCL-2 protein. Notably, venetoclax, an extremely high-affinity BCL-2 inhibitor, stands out particularly for its high therapeutic index, especially when combined with hypomethylating agents like azacytidine and decitabine, among older patients and even young patients with comorbidities that preclude intensive chemotherapy regimens. Once more, because the new AML model is evolving, venetoclax is being used more with high-intensity chemotherapy even in young patients, at any age. Areas covered. This review summarizes the progress in AML targeting the intrinsic apoptosis pathway with current and developing BCL-2 inhibitors, as well as their clinical applications in combination therapies.
EXPERT OPINION: While venetoclax has made significant progress in treating AML, ongoing clinical research is moving this agent into first-line combination treatments. Notably, the lack of response to this agent and the development of acquired resistance remain significant concerns. Although specific gene mutations strongly predict clinical response, research is ongoing into predictive biomarkers and new drug combinations that work synergistically. Emerging therapies targeting BCL-2 also aim to maximize treatment benefits and address issues related to venetoclax resistance.

Keywords:  BH3 mimetics; acute myeloid leukemia; hypomethylating agents; intensive chemotherapy; targeted therapies; venetoclax

DOI:  https://doi.org/10.1080/14656566.2025.2582022
Mol Biomed. 2025 Oct 27. 6(1): 87

Dihydroorotate dehydrogenase inhibition activates STING pathway and pyroptosis to enhance NK cell-dependent tumor immunotherapy.

Yongrui Hai, Ruizhuo Lin, Weike Liao, Shuo Fu, Renming Fan, Guiquan Ding, Junyan Zhuang, Bingjie Zhang, Yi Liu, Junke Song, Gaofei Wei.

  Cancer cells rely heavily on de novo pyrimidine synthesis. Inhibiting pyrimidine metabolism directly suppresses tumor growth and fosters immune activation within the tumor microenvironment. Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine synthesis pathway. Inhibiting DHODH can reverse immune suppression and trigger a mild innate immune response. However, the impact of DHODH inhibition on natural killer (NK) cells remains to be explored. In this study, we found that DHODH inhibition promoted NK cell infiltration into tumors efficiently. Mechanistically, DHODH suppression induced mitochondrial oxidative stress, leading to mitochondrial DNA (mtDNA) release into the cytoplasm through voltage-dependent anion channel (VDAC) oligomerization and caspase-3 activation. This subsequently activated the stimulator of interferon gene (STING) pathway, triggered ferroptosis, and induced gasdermin E (GSDME) mediated pyroptosis in cancer cells. These changes collectively facilitated NK cell recruitment. Furthermore, infiltrated NK cells enhanced GSDME-dependent pyroptosis in tumor cells through granzyme release, establishing a positive feedback loop that amplified anti-tumor immunity. Additionally, we developed EA6, a novel DHODH inhibitor that is more effective at promoting NK cell infiltration. In summary, this study reveals that targeting pyrimidine metabolism activates a novel mechanism involving pyroptosis-ferroptosis crosstalk and STING pathway activation to enhance NK cell-mediated immunity. These finding opens new avenues for enhancing the efficacy of targeted nucleotide metabolism in cancer therapy.

Keywords:  CGAS-STING pathway; DHODH; NK cells; Pyrimidine metabolism; Pyroptosis

DOI:  https://doi.org/10.1186/s43556-025-00339-7
Front Oncol. 2025 ;15 1638108

The cancer-induced lactate load and oncologic remodeling hypothesis: lactate as a driver of biosynthesis and epigenetics in cancer.

Hüseyin Aydin.

   Background: Cancer cells undergo profound metabolic reprogramming to sustain proliferation, redox homeostasis, and epigenetic remodeling. While the Warburg effect and glutaminolysis have long been recognized as central paradigms, the anabolic and regulatory role of lactate under normoxic conditions remains poorly defined.
Hypothesis: The Cancer-Induced Lactate Load and Oncologic Remodeling (CILLO) hypothesis proposes that lactate, either imported through MCT1 or produced endogenously, is oxidized to pyruvate by LDHB and subsequently carboxylated to oxaloacetate (OAA) by pyruvate carboxylase. OAA then acts as a metabolic hub driving malate-dependent NADPH production, aspartate synthesis for nucleotide metabolism, activation of the serine/glycine/folate cycle, lipogenesis, and S-adenosylmethionine-mediated epigenetic modifications. In this framework, lactate is no longer a mere by-product of glycolysis but a central integrator of anabolic flux, redox balance, and chromatin dynamics.
Conclusion: The CILLO hypothesis unifies previously fragmented mechanisms into a coherent paradigm, emphasizing lactate-derived carbon skeletons as active drivers of tumor growth and metabolic plasticity. Key rate-limiting steps-MCT1-mediated uptake, LDHB-dependent oxidation, PC-driven anaplerosis, and PEPCK-M-mediated cataplerosis-emerge as therapeutic nodes for intervention. This model not only advances our understanding of cancer metabolism but also suggests novel strategies for biomarker development, metabolic imaging, and targeted therapies. By reframing lactate as a central determinant of oncologic remodeling, the CILLO hypothesis provides a foundation for translational advances in oncology and personalized medicine.

Keywords:  CILLO hypothesis; epigenetic regulation; lactate metabolism; metabolic reprogramming; oxaloacetate; pyruvate carboxylase; redox balance

DOI:  https://doi.org/10.3389/fonc.2025.1638108