bims-mibica 2025-07-27 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–07–27
twenty-two papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Mitochondrial CLK2 promotes chemotherapy resistance in colorectal Cancer by regulating oxidative phosphorylation and ferroptosis.
One-Carbon Metabolism Inhibition Depletes Purines and Results in Profound and Prolonged Ewing Sarcoma Growth Suppression.
Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.
Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism.
Targeting the WSB2-NOXA axis in cancer cells for enhanced sensitivity to BCL-2 family protein inhibitors.
Metastatic breast cancer cells are selectively dependent on the mitochondrial cristae-shaping protein OPA1.
Development of novel mitochondrial pyruvate carrier inhibitors for breast cancer treatment.
Amino Acid Metabolism in Liver Mitochondria: From Homeostasis to Disease.
The unexpected role of Na+ in mitochondrial bioenergetics, ROS production and homeostasis.
Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase.
ATP Supply from Cytosol to Mitochondria Is an Additional Role of Aerobic Glycolysis to Prevent Programmed Cell Death by Maintenance of Mitochondrial Membrane Potential.
Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies.
The peculiar properties of mitochondrial carriers of the SLC25 family.
Mitochondria as Regulators of Nonapoptotic Cell Death in Cancer.
Understanding and Targeting BCL2-inhibitor Resistance in Chronic Lymphocytic Leukemia.
Metabolic Effects of Succinate Dehydrogenase Loss in Cancer.
POLRMT enhances lenvatinib resistance in hepatocellular carcinoma cells by maintaining mitochondrial ATP production.
TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger.
α-Ketoglutarate promotes amino acid depletion and suppresses B-cell lymphoma growth and development.
Cell type-specific purifying selection of synonymous mitochondrial DNA variation.
ATP synthesis driven by atmospheric hydrogen concentrations.

J Mol Histol. 2025 Jul 23. 56(4): 239

Mitochondrial CLK2 promotes chemotherapy resistance in colorectal Cancer by regulating oxidative phosphorylation and ferroptosis.

Xingchun Xiao, Qiling Lin, Wentai Shi.



Keywords:  Chemotherapy resistance; Colorectal cancer; Ferroptosis; Mitochondrial metabolism; Mitochondrial respiration

DOI:  https://doi.org/10.1007/s10735-025-10533-0
Cancer Res Commun. 2025 Jul 23.

One-Carbon Metabolism Inhibition Depletes Purines and Results in Profound and Prolonged Ewing Sarcoma Growth Suppression.

Sara Zirpoli, Noah Copperman, Shrey Patel, Alexander Forrest, Zhanjun Hou, Larry H Matherly, David M Loeb, Antonio Di Cristofano.

Ewing sarcoma (EWS) is the second most common primary bone malignancy in adolescents and young adults. Patients who present with localized disease have experienced a steadily improving survival rate over the years, whereas those who present with metastatic disease have the same dismal prognosis as 30 years ago, with long term survival rates less than 20%, despite maximal intensification of chemotherapy. Thus, novel treatment approaches are a significant unmet clinical need. Targeting metabolic differences between EWS and normal cells offers a promising approach to improve outcomes for these patients. One-carbon metabolism utilizes serine and folate to generate glycine and tetrahydrofolate (THF)-bound one-carbon units required for de novo nucleotide biosynthesis. Elevated expression of several one-carbon metabolism genes is significantly associated with reduced survival in EWS patients. We show that both genetic and pharmacological inhibition of a key enzyme of the mitochondrial arm of the one-carbon metabolic pathway, serine hydroxymethyltransferase 2 (SHMT2), leads to substantial inhibition of EWS cell proliferation and colony-forming ability, and that this effect is primarily caused by depletion of glycine and one-carbon units required for synthesis of purine nucleotides. Inhibition of one-carbon metabolism at a different node, using the clinically relevant dihydrofolate reductase inhibitor Pralatrexate, similarly yields a profound growth inhibition, with depletion of thymidylate and purine nucleotides. Genetic depletion of SHMT2 dramatically impairs tumor growth in a xenograft model of EWS. Together, these data establish dependence on one-carbon metabolism as a novel and targetable vulnerability of EWS cells, which can be exploited for therapy.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0218
Nat Commun. 2025 Jul 21. 16(1): 6700

Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.

Yingyuan Sun, Yaru Wang, Zheng Xing, Dongyu Li, Rong Wang, Baozhi Chen, Ning Zhou, Alyssa Ayala, Benjamin P Tu, Xiaofeng Qi.

The Mitochondrial Pyruvate Carrier (MPC) bridges cytosolic and mitochondrial metabolism by transporting pyruvate into mitochondria for ATP production and biosynthesis of various essential molecules. MPC functions as a heterodimer composed of MPC1 and MPC2 in most mammalian cells. Here, we present the cryogenic electron microscopy (cryo-EM) structures of the human MPC1-2 complex in the mitochondrial intermembrane space (IMS)-open state and the inhibitor-bound in the mitochondrial matrix-open state. Structural analysis shows that the transport channel of MPC is formed by the interaction of transmembrane helix (TM) 1 and TM2 of MPC1 with TM2 and TM1 of MPC2, respectively. UK5099, a potent MPC inhibitor, shares the same binding site with pyruvate at the matrix side of the transport channel, stabilizing MPC in its matrix-open conformation. Notably, a functional W82F mutation in MPC2 leads to the complex in an IMS-open conformation. Structural comparisons across different conformations, combined with yeast rescue assays, reveal the mechanisms of substrate binding and asymmetric conformational changes in MPC during pyruvate transport across the inner mitochondrial membrane (IMM) as well as the inhibitory mechanisms of MPC inhibitors.

DOI: https://doi.org/10.1038/s41467-025-61939-z
Res Sq. 2025 Jul 15. pii: rs.3.rs-7042684. [Epub ahead of print]

Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.

Tim Heden, Melina Mancini, Cameron McCall, Robert Noland, Wagner Dontas.

Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.

DOI: https://doi.org/10.21203/rs.3.rs-7042684/v1
Cell Chem Biol. 2025 Jul 17. pii: S2451-9456(25)00201-6. [Epub ahead of print]32(7): 902-904

Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism.

Riley J Wedan, Sara M Nowinski.

Mitochondrial NADPH is abundant, but the reason why was uncertain. In a study published in Nature Cell Biology, Kim et al.1 identified an important role of NADK2-derived mitochondrial NADPH in mitochondrial fatty acid synthesis (mtFAS) through direct quantification of the products built by mtFAS. This work opens the door to understanding how NADK2, mitochondrial NADPH, and mtFAS regulate mitochondrial function.

DOI: https://doi.org/10.1016/j.chembiol.2025.06.006
Elife. 2025 Jul 23. pii: RP98372. [Epub ahead of print]13

Targeting the WSB2-NOXA axis in cancer cells for enhanced sensitivity to BCL-2 family protein inhibitors.

Dongyue Jiao, Kun Chang, Jiamin Jin, Yingji Chen, Mo Ren, Yucong Zhang, Kun Gao, Yaoting Xu, Lixin Wang, Chenji Wang.

  Anti-apoptotic B-cell lymphoma-2 (BCL-2) family proteins are frequently overexpressed in various cancers, playing a pivotal role in cancer initiation and progression, as well as intrinsic or acquired resistance to therapy. Although inhibitors targeting BCL-2, such as Venetoclax, have shown efficacy in hematological malignancies, their therapeutic potential in solid tumors remains limited. Identifying novel molecular targets to overcome resistance to these inhibitors is of significant clinical importance. Here, we provide evidence of a strong synthetic lethality between WSB2, a previously underexplored substrate-binding receptor of the Cullin 5-RBX2-Elongin B/C (CRL5) E3 ubiquitin ligase complex, and anti-apoptotic BCL-2 family proteins. Mechanistically, WSB assembles a CRL5 E3 ubiquitin ligase complex that facilitates the ubiquitination and subsequent proteasomal degradation of NOXA, a pro-apoptotic BCL-2 family protein. Loss of WSB2 leads to a substantial accumulation of NOXA in both cultured cell lines and knockout mouse tissues. While WSB2 deficiency alone does not significantly impact spontaneous apoptosis, it sensitizes cells to apoptosis when anti-apoptotic BCL-2 family proteins are either genetically depleted or pharmacologically inhibited. Moreover, WSB2 is overexpressed in several human cancer types. These findings identify WSB2 as a critical regulator of mitochondrial apoptosis and reveal the dysregulation of the WSB2-NOXA axis as a key factor contributing to apoptosis resistance in cancer cells. Targeting both WSB2 and anti-apoptotic BCL-2 family proteins holds promising therapeutic potential for overcoming resistance in human cancers.

Keywords:  Venetoclax; WSB2; apoptosis; cell biology; drug resistance; human; ubiquitination

DOI:  https://doi.org/10.7554/eLife.98372
Cell Death Dis. 2025 Jul 21. 16(1): 539

Metastatic breast cancer cells are selectively dependent on the mitochondrial cristae-shaping protein OPA1.

Antigoni Diokmetzidou, Aurora Maracani, Anna Pellattiero, Mauricio Cardenas-Rodriguez, Erwan A Rivière, Luca Scorrano.

In breast cancer, the inner mitochondrial membrane fusion protein Optic Atrophy 1 (OPA1) is upregulated and its inhibition reverses acquired chemoresistance. However, it remains unclear whether OPA1 inhibition also targets normal breast cells. We show that OPA1 upregulation is a hallmark of metastatic breast cancer cells, which are selectively susceptible to OPA1 inhibition compared to isogenic normal or localized tumor cells. In an isogenic model spanning normal, transformed, and metastatic breast cancer cells, levels of Mitofusin 1 (MFN1) progressively declined while dynamin related protein 1 (DRP1) became increasingly active, correlating with fragmented mitochondria during cancer progression. Meanwhile, OPA1 levels were elevated in invasive cells characterized by mitochondrial fragmentation, tight cristae, and high respiration. OPA1 deletion selectively reduced metastatic cells mitochondrial respiration, proliferation, and migration. Specific OPA1 inhibitors MYLS22 and Opitor-0 diminished migration and increased death of metastatic cells, underscoring OPA1 as a selective vulnerability of metastatic breast cancer.

DOI: https://doi.org/10.1038/s41419-025-07878-5
J Biol Chem. 2025 Jul 16. pii: S0021-9258(25)02336-1. [Epub ahead of print] 110486

Development of novel mitochondrial pyruvate carrier inhibitors for breast cancer treatment.

Tanner J Schumacher, Zachary S Gardner, Jon Rumbley, Conor T Ronayne, Venkatram R Mereddy.

  Reprogrammed metabolism of cancer cells offers a unique target for pharmacological intervention. The mitochondrial pyruvate carrier (MPC) plays important roles in cancer progression by transporting cytosolic pyruvate into the mitochondria for use in the TCA cycle. In the current study, a series of novel fluoro-substituted aminocarboxycoumarin derivatives have been evaluated for their mitochondrial pyruvate carrier (MPC) inhibition properties. Our studies indicate that the aminocarboxycoumarin template elicits potent MPC inhibitory characteristics, and specifically, structure activity relationship studies show that the N-methyl-N-benzyl structural template provides the optimal inhibitory capacity. Further respiratory experiments demonstrate that candidate compounds specifically inhibit pyruvate driven respiration without substantially affecting other metabolic fuels, consistent with MPC inhibition. Further, computational inhibitor docking studies illustrate that aminocarboxycoumarin binding characteristics are nearly identical to that of classical MPC inhibitor UK5099 bound to human MPC, recently determined by cryoEM. The lead candidate C5 elicits cancer cell proliferation inhibition specifically in monocarboxylate transporter 1 (MCT1) expressing murine breast cancer cells 4T1 and 67NR, consistent with its ability to accumulate intracellular lactate. In vivo tumor growth studies illustrate that C5 significantly reduces the tumor burden in two syngeneic murine tumor models with 4T1 and 67NR cells. These studies provide novel MPC inhibitors with potential for anticancer applications in MCT1 expressing breast cancer tumor models.

Keywords:  aminocarboxycoumarin; breast cancer; mitochondrial pyruvate carrier; tumor metabolism

DOI:  https://doi.org/10.1016/j.jbc.2025.110486
Metabolites. 2025 Jul 02. pii: 446. [Epub ahead of print]15(7):

Amino Acid Metabolism in Liver Mitochondria: From Homeostasis to Disease.

Ranya Erdal, Kıvanç Birsoy, Gokhan Unlu.

  Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics. These functions depend on tightly regulated mitochondrial processes, including amino acid catabolism, ammonia clearance via the urea cycle, and transport through specialized solute carriers. Genetic disruptions in these pathways underlie a range of inborn errors of metabolism, often resulting in systemic toxicity and neurological dysfunction. Here, we review the physiological functions of hepatic mitochondrial amino acid metabolism, with a focus on subcellular compartmentalization, disease mechanisms, and therapeutic strategies. We discuss how emerging genetic and metabolic interventions-including dietary modulation, cofactor replacement, and gene therapy-are reshaping treatment of liver-based metabolic disorders. Understanding these pathways offers mechanistic insights into metabolic homeostasis and reveals actionable vulnerabilities in metabolic disease and cancer.

Keywords:  amino acids; cancer; inborn errors of metabolism; liver; metabolism; mitochondria

DOI:  https://doi.org/10.3390/metabo15070446
Arch Biochem Biophys. 2025 Jul 17. pii: S0003-9861(25)00257-7. [Epub ahead of print]772 110544

The unexpected role of Na+ in mitochondrial bioenergetics, ROS production and homeostasis.

Pablo Hernansanz-Agustín.

  In the last few years, mitochondrial Na+ has emerged as an important player for cellular adaptation and bioenergetics. Previously, the role of Na+ was confined to the co-maintenance of plasma membrane potential. Now, it has expanded, particularly in the mitochondria, after its discovery as a second messenger. During acute hypoxia, Na+ enters in the mitochondrial matrix, interacts with phospholipids, regulating the inner mitochondrial membrane fluidity and reactive oxygen species (ROS) production by the mitochondrial electron transport chain. In addition, we have recently shown that, in normal conditions, Na+ also have deep implications in bioenergetics. It forms a gradient across the inner mitochondrial membrane which accounts for up to half of the ΔΨmt. This gradient is built up by the activity of the mitochondrial Na+-specific Na+/H+ exchanger (NHE), which partially dissipates the H+ gradient (ΔpH) to generate the Na+ gradient (ΔNa+). Interestingly, the molecular identity of this exchanger is complex I (CI). These roles of mitochondrial Na+ allow the control over mitochondrial Ca2+ content and open a novel relationship with physiology and disease. Overall, this review focuses on how mitochondrial Na+ regulates bioenergetics, mitochondrial ion handling and ROS levels, as well as its consequences for cell life and death.

Keywords:  Bioenergetics; Ca(2+); Mitochondria; Na(+); Reactive oxygen species; ion handling

DOI:  https://doi.org/10.1016/j.abb.2025.110544
J Clin Invest. 2025 Jul 22. pii: e190215. [Epub ahead of print]

Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase.

Chao-Chieh Lin, Yi-Tzu Lin, Ssu-Yu Chen, Yasaman Setayeshpour, Yubin Chen, Denise E Dunn, Taylor Nguyen, Alexander A Mestre, Adrija Banerjee, Lalitha Guruprasad, Erik J Soderblom, Guo-Fang Zhang, Chen-Yong Lin, Valeriy Filonenko, Suh Young Jeong, Scott R Floyd, Susan J Hayflick, Ivan Gout, Jen-Tsan Chi.

  The cystine-xCT transporter-glutathione (GSH)-GPX4 axis is the canonical pathway protecting cells from ferroptosis. While GPX4-targeting ferroptosis-inducing compounds (FINs) act independently of mitochondria, xCT-targeting FINs require mitochondrial lipid peroxidation, though the mechanism remains unclear. Since cysteine is also a precursor for coenzyme A (CoA) biosynthesis, here, we demonstrated that CoA supplementation selectively prevented ferroptosis triggered by xCT inhibition by regulating the mitochondrial thioredoxin system. Our data showed that CoA regulated the in vitro enzymatic activity of mitochondrial thioredoxin reductase (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolished its enzymatic activity and ability to protect cells against ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2. Furthermore, the fibroblasts from patients with disrupted CoA metabolism demonstrated increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis led to an oxidized thioredoxin system, increased mitochondrial lipid peroxidation, and loss of cell viability, which were all rescued by ferrostatin-1. These findings identified CoA-mediated post-translational modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.

Keywords:  Amino acid metabolism; Cell biology; Cell stress; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI190215
Metabolites. 2025 Jul 07. pii: 461. [Epub ahead of print]15(7):

ATP Supply from Cytosol to Mitochondria Is an Additional Role of Aerobic Glycolysis to Prevent Programmed Cell Death by Maintenance of Mitochondrial Membrane Potential.

Akane Sawai, Takeo Taniguchi, Kohsuke Noguchi, Taisuke Seike, Nobuyuki Okahashi, Masak Takaine, Fumio Matsuda.

  Eukaryotic cells generate ATP primarily via oxidative and substrate-level phosphorylation. Despite the superior efficiency of oxidative phosphorylation, eukaryotic cells often use both pathways as aerobic glycolysis, even in the presence of oxygen. However, its role in cell survival remains poorly understood. Objectives: In this study, aerobic glycolysis was compared between the Warburg effect in breast cancer cells (MCF7) and the Crabtree effect in a laboratory strain of Saccharomyces cerevisiae (S288C). Methods: The metabolic adaptations of MCF7 and S288C cells were compared following treatment with electron transport chain inhibitors, including FCCP, antimycin A, and oligomycin. Results: MCF7 and S288C cells exhibited strikingly similar metabolic rewiring toward substrate-level phosphorylation upon inhibitor treatment, suggesting that mitochondrial oxidative phosphorylation and cytosolic substrate-level phosphorylation communicate through a common mechanism. Measurement of mitochondrial membrane potential (MMP) and ATP concentrations further indicated that cytosolic ATP was transported into the mitochondria under conditions of reduced electron transport chain activity. This ATP was likely utilized in the reverse mode of H+/ATPase to maintain MMP, which contributed to the avoidance of programmed cell death. Conclusions: These results suggest that the ATP supply to mitochondria plays a conserved role in aerobic glycolysis in yeast and mammalian cancer cells. This mechanism likely contributes to cell survival under conditions of fluctuating oxygen availability.

Keywords:  Saccharomyces cerevisiae; aerobic glycolysis; breast cancer cells; metabolic rewiring; mitochondrial membrane potential; programmed cell death; reverse mode of H+/ATPase

DOI:  https://doi.org/10.3390/metabo15070461
Leukemia. 2025 Jul 24.

Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies.

Stephen J F Chong, Jolin X H Lai, Kartini Iskandar, Benedict J Leong, Chuqi Wang, Yuhan Wang, Romain Guièze, Deepika Raman, Rachel H F Lim, Catherine J Wu, Wee Joo Chng, Alice M S Cheung, Charles Chuah, Matthew S Davids, Shazib Pervaiz.

Resistance to the Bcl-2-specific inhibitor, Venetoclax (VEN), poses a therapeutic challenge in the management of chronic lymphocytic leukemia and acute myeloid leukemia. Although VEN resistance has been linked to Mcl-1 upregulation, thereby switching survival dependence from Bcl-2 to Mcl-1, the mechanism underlying increased Mcl-1 expression remains elusive. Given that changes in cellular redox state affect cancer cell fate, we investigated the crosstalk between intracellular redox milieu and Mcl-1 upregulation in VEN-resistant cells. Results show that increased Mcl-1 protein levels in VEN-resistant hematologic malignant cells are associated with elevated intracellular superoxide (O2.-) levels. Validating that, augmenting intracellular O2.- in VEN-sensitive cells increases Mcl-1 phosphorylation at threonine-163 (T163pMcl-1) and protein stability via reduced Mcl-1 ubiquitination and degradation. Furthermore, redox-activated AKT/PKB is implicated in O2.--induced T163pMcl-1, as reducing intracellular O2.- or inhibiting AKT significantly decreases T163pMcl-1 and Mcl-1 accumulation, which amplifies mitochondrial apoptotic priming and restores VEN sensitivity. Importantly, combination therapy with AKT inhibitor, capivasertib, and VEN reduced VEN-resistant cells systemically and prolonged survival in a murine model. Collectively, a novel redox-dependent mechanism of Mcl-1 stability is demonstrated for the acquisition of VEN resistance, which has therapeutic implications for employing redox modulating strategies and AKT inhibitors against VEN-resistant hematologic malignancies.

DOI: https://doi.org/10.1038/s41375-025-02694-4
Biochem J. 2025 Jul 23. pii: BCJ20253171. [Epub ahead of print]482(15):

The peculiar properties of mitochondrial carriers of the SLC25 family.

Edmund R S Kunji, Vasiliki Mavridou, Martin S King, Camila Cimadamore-Werthein, Stephany Jaiquel Baron, Scott A Jones, Alannah C King, Roger Springett, Deepak Chand, Shane M Palmer, Denis Lacabanne, Sotiria Tavoulari, Jonathan J Ruprecht.

  With 53 members, the SLC25 mitochondrial carriers form the largest solute carrier family in humans. They transport a wide variety of substrates across the mitochondrial inner membrane to generate chemical energy and to supply molecules and ions for growth and maintenance of cells. They are among the smallest transporters in nature, yet they translocate some of the largest molecules without proton leak. With one exception, they are monomeric and have an unusual three-fold pseudo-symmetric structure. These carriers also have a unique transport mechanism, which is facilitated by six structural elements, meaning that all transmembrane helices move separately, but in a co-ordinated way. In addition, there are three functional elements that are an integral part of the alternating access mechanism, which opens and closes the carrier to the mitochondrial matrix or the intermembrane space. The first is a matrix gate, comprising the matrix salt bridge network and glutamine braces on transmembrane helices H1, H3 and H5. The second is a cytoplasmic gate, containing the cytoplasmic salt bridge network and tyrosine braces on transmembrane helices H2, H4 and H6. The third functional element is a single central substrate-binding site, the access to which is controlled by the opening and closing of the two gates in an alternating way. The electrostatic properties of the binding site facilitate the exchange of charged substrates across the inner membrane in the presence of a high membrane potential. Here, we discuss the extraordinary features of mitochondrial carriers, providing new insights into one of the most complex and dynamic transport mechanisms in nature.

Keywords:  bioenergetics; mitochondria; oxidative phosphorylation; translocases; translocators; transport mechanism

DOI:  https://doi.org/10.1042/BCJ20253171
MedComm (2020). 2025 Aug;6(8): e70244

Mitochondria as Regulators of Nonapoptotic Cell Death in Cancer.

Saloni Malla, Rabin Neupane, Saloni Sood, Noor Hussein, Mariam Abou-Dahech, David Terrero, Charles R Ashby, R Jayachandra Babu, Amit K Tiwari.

  Mitochondria are involved in cell survival and metabolic processes including adenosine triphosphate production, heme biosynthesis, reactive oxygen species, and iron and calcium homeostasis. Although mitochondria are well known to contribute to apoptosis, a growing body of evidence indicates that mitochondria modulate nonapoptotic cell death (NACD) mechanisms, including autophagy, necroptosis, ferroptosis, paraptosis, pyroptosis, parthanatosis, and cuproptosis. These NACD pathways differ in molecular triggers, morphological characteristics, and immunological consequences, but they all involve mitochondria. For example, mitochondrial ROS and lipid peroxidation play a role in ferroptosis, whereas mitochondrial depolarization and the release of apoptosis inducing factor are paramount to parthanatosis. Mitochondrial swelling is a hallmark of paraptosis, whereas mitochondrial disruption is associated with pyroptosis. Autophagy, though primarily a survival mechanism, is also regulated by mitochondrial dynamics in cancer cells. In cuproptosis, mitochondrial protein aggregates when iron-sulfur cluster proteins are disrupted, resulting in copper-dependent cell death. There are many factors that influence NACD, including mitochondrial membrane potential, bioenergetics, calcium flux, metabolites, and interactions with the endoplasmic reticulum. The review comprehensively summarizes our understanding of mitochondrial and NACD interactions, particularly in cells resistant to classical apoptosis agents. Therapeutic vulnerabilities associated with mitochondria-mediated NACD could lead to next-generation therapies.

Keywords:  autophagy; cancer; ferroptosis; mitochondria; necroptosis; nonapoptotic cell death

DOI:  https://doi.org/10.1002/mco2.70244
Hematol Oncol Clin North Am. 2025 Jul 22. pii: S0889-8588(25)00085-1. [Epub ahead of print]

Understanding and Targeting BCL2-inhibitor Resistance in Chronic Lymphocytic Leukemia.

Alexander F Vom Stein, Lukas P Frenzel.

  Chronic lymphocytic leukemia (CLL) treatment has evolved with the introduction of venetoclax, a selective BCL-2 inhibitor capable of inducing apoptosis in CLL cells. However, resistance has emerged as a significant clinical obstacle. Here, we delineate the multifactorial basis of venetoclax resistance in CLL by exploring genetic mutations, epigenetic alterations, microenvironmental protection, metabolic rewiring, and downstream signaling adaptations. Furthermore, we examine strategies to overcome resistance, including drug combinations, next-generation BCL-2 inhibitors, and novel immunotherapeutic approaches. Finally, we consider the clinical implications of emerging resistance patterns and discuss future directions in a personalized therapy.

Keywords:  BCL2; Chronic lymphocytic leukemia; Resistance; Venetoclax

DOI:  https://doi.org/10.1016/j.hoc.2025.06.001
J Cell Physiol. 2025 Jul;240(7): e70066

Metabolic Effects of Succinate Dehydrogenase Loss in Cancer.

Adam Chatoff, Daniel S Kantner, Nathaniel W Snyder, Lori Rink.

  Succinate dehydrogenase (SDH) is both Complex II in the electron transport chain (ETC) and a key metabolic enzyme in the tricarboxylic acid cycle. SDH is a heterotetrameric enzyme consisting of four subunits SDHA, SDHB, SDHC, and SDHD, all encoded in the nuclear genome. In addition, the SDH complex requires two assembly factors, SDHAF1 and SDHAF2, which are required for assembly of SDHA and SDHB onto the inner mitochondrial-embedded subunits SDHC and SDHD. Once assembled, SDH catalyzes the conversion of succinate to fumarate coupled to the reduction of ubiquinone to ubiquinol via FAD/FADH2 and ultimately the generation of ATP via ATP synthase through a functioning ETC. Given the unique dual metabolic role of SDH, loss of activity results in major metabolic rewiring, potentially uncovering metabolic vulnerabilities that could be targeted for pharmacological manipulation in disease states. SDH is a tumor suppressor and SDH-loss is a driver of oncogenesis for cancers including pheochromocytomas, paragangliomas, gastrointestinal stromal tumors, and clear cell renal cell carcinomas. SDH deficiency also plays a role in the pathogenesis in non-neoplastic diseases, including Leigh syndrome and other neurometabolic disorders. Considering the implications of SDH function in both normal physiology and disease, understanding SDH function has fundamental and translational implications. This review seeks to summarize SDH deficiency, focusing on the role SDH plays in metabolism, the metabolic consequences of SDH deficiency, the proteomic consequences of SDH loss, thereby highlight potential therapeutic vulnerabilities in SDH-deficient cells.

Keywords:  Complex II; clear cell renal cell carcinoma; electron transport chain; gastrointestinal stromal tumors; leigh syndrome; pheochromocytomas/paragangliomas; succinate dehydrogenase; tricarboxylic acid cycle

DOI:  https://doi.org/10.1002/jcp.70066
Life Sci. 2025 Jul 22. pii: S0024-3205(25)00511-9. [Epub ahead of print] 123876

POLRMT enhances lenvatinib resistance in hepatocellular carcinoma cells by maintaining mitochondrial ATP production.

Rui Wang, Boyu Chen, Yibing Pan, Meng Wang, Yunyun Xiao, Dongni Shi, Yanling Wen, Ying Ouyang, Xiangfu Chen, Yue Li, Libing Song, Binhui Xie.

  Lenvatinib is one of first-line therapeutic agents for advanced hepatocellular carcinoma (HCC), yet lenvatinib resistance of tumor resulting in a weak response on many patients. Mitochondrial energy metabolism is environmentally adaptable and has been shown to play a crucial role in tumor resistance to therapy. Therefore, identification of the key regulator of mitochondrial energy metabolism during lenvatinib resistance provides a novel target for drug-resistant HCC. We found that POLRMT upregulated in lenvatinib-resistant HCC and is associated with poor patient prognosis. POLRMT increased oxidative phosphorylation levels and mitochondrial ATP production through transcriptional upregulation of respiratory chain complexes, which counteracted lenvatinib-induced cellular ATP decrease and the AMPK-caspase 3 signaling pathway. Furthermore, using IMT1B, a specific inhibitor of POLRMT, resensitized the resistant HCC to lenvatinib in vitro and in vivo. This study highlights the critical role of POLRMT in maintaining mitochondrial ATP production, and suggests that POLRMT could serve as a novel prognostic biomarker and potential therapeutic target for lenvatinib-resistant HCC.

Keywords:  Lenvatinib resistance; Mitochondria; Oxidative phosphorylation; POLRMT

DOI:  https://doi.org/10.1016/j.lfs.2025.123876
Nat Cell Biol. 2025 Jul 21.

TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger.

Jim Lu Zhang, Yu-Chen Chang, Po-Hsuan Lai, Han-I Yeh, Chen-Wei Tsai, Yu-Lun Huang, Tsung-Yun Liu, I-Chi Lee, North Foulon, Yan Xu, Bing Rao, Hsiu-Man Shih, Yung-Chi Tu, Andres V Reyes, Shou-Ling Xu, Liang Feng, Ming-Feng Tsai.

Mitochondria export Ca2+ via Na+/Ca2+ exchange machinery (mito-NCX) to regulate intracellular Ca2+ signalling and mitochondrial Ca2+ homeostasis. TMEM65 has recently been implicated as essential for mito-NCX, but its mechanisms and roles remain unclear. Here we show that TMEM65 depletion severely impairs mito-NCX. TMEM65 is highly expressed in the heart and brain but absent in the liver, correlating with mito-NCX activity in these tissues. Biochemical and functional analyses reveal that TMEM65 forms a homodimer, containing plausible ion-coordinating residues critical for function. Heterologous expression of TMEM65 induces Na+/Ca2+ exchange in cells lacking native mito-NCX activity. Moreover, purified, liposome-reconstituted TMEM65 exhibits key mito-NCX features. We further identify the binding site for CGP-37157, a potent, widely used mito-NCX inhibitor. Finally, TMEM65 deletion elevates mitochondrial Ca2+ and primes mitochondria to permeability transition. These findings firmly establish TMEM65 as the protein mediating mito-NCX, offering a new therapeutic target for diseases associated with mitochondrial Ca2+ dysregulation.

DOI: https://doi.org/10.1038/s41556-025-01721-x
Blood. 2025 Jul 23. pii: blood.2024028069. [Epub ahead of print]

α-Ketoglutarate promotes amino acid depletion and suppresses B-cell lymphoma growth and development.

Carine Jaafar, Purushoth Ethiraj, Zhijun Qiu, An-Ping Lin, Pedro Simonis Seabra Martins Ferrari, Ricardo Aguiar.

Targeting metabolic dependencies and "starving" malignant cells have long been considered as potential strategies to treat cancer. However, with rare exceptions, the implementation of these maneuvers has been fraught with limited activity and lack of specificity. Multiple cytoplasmic and mitochondrial transaminases catalyze reactions that lead to amino acid catabolism. These enzymes use alpha-ketoglutarate (αKG) as a nitrogen acceptor, and accumulation of the competitive inhibitor metabolite D-2-HG perturbs their function. We postulated that exogenous αKG supplementation would influence the directionality of these reactions and deplete amino acids in cancer cells. Using B cell lymphoma as a model system, we found that αKG mediates a rapid and sustained amino acid depletion, principally of aspartate and branched-chain leucine, valine and isoleucine. The decrease in leucine levels influenced MTORC1 sub-cellular movement, suppressed its activity and associated with inhibition of B cell lymphoma growth in vitro and in vivo Increasing import of aspartate or leucine levels in the lymphoma cells, genetically forcing MTORC1 lysosomal localization or blocking leucine catabolism through BCAT2 deletion, all blunted the anti-lymphoma effects of αKG. In addition, long term dietary supplementation of αKG, a toxicity free strategy, significantly hindered lymphoma development in Eµ-Myc mice, in association with amino acid perturbation and impaired energy generation. We posit that αKG supplementation, which has been shown to improve health and lifespan in mice, also encodes marked anti-cancer properties.

DOI: https://doi.org/10.1182/blood.2024028069
Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2505704122

Cell type-specific purifying selection of synonymous mitochondrial DNA variation.

Caleb A Lareau, Patrick Maschmeyer, Yajie Yin, Jacob C Gutierrez, Ryan S Dhindsa, Anne-Sophie Gribling-Burrer, Sebastian Zielinski, Yu-Hsin Hsieh, Lena Nitsch, Veronika Dimitrova, Benan Nalbant, Frank A Buquicchio, Tsion Abay, Robert R Stickels, Jacob C Ulirsch, Patrick Yan, Fangyi Wang, Zhuang Miao, Katalin Sandor, Bence Daniel, Vincent Liu, Paul L Mendez, Petra Knaus, Manpreet Meyer, William J Greenleaf, Anshul Kundaje, Redmond P Smyth, Mathias Munschauer, Leif S Ludwig, Ansuman T Satpathy.

  While somatic variants are well-characterized drivers of tumor evolution, their influence on cellular fitness in nonmalignant contexts remains understudied. We identified a mosaic synonymous variant (m.7076A > G) in the mitochondrial DNA (mtDNA)-encoded cytochrome c-oxidase subunit 1 (MT-CO1, p.Gly391=), present at homoplasmy in 47% of immune cells from a healthy donor. Single-cell multiomics revealed strong, lineage-specific selection against the m.7076G allele in CD8+ effector memory T cells, but not other T cell subsets, mirroring patterns of purifying selection of pathogenic mtDNA alleles. The limited anticodon diversity of mitochondrial tRNAs forces m.7076G translation to rely on wobble pairing, unlike the Watson-Crick-Franklin pairing used for m.7076A. Mitochondrial ribosome profiling confirmed stalled translation of the m.7076G allele. Functional analyses demonstrated that the elevated translational and metabolic demands of short-lived effector T cells (SLECs) amplify dependence on MT-CO1, driving this selective pressure. These findings suggest that synonymous variants can alter codon syntax, impacting mitochondrial physiology in a cell type-specific manner.

Keywords:  immunology; mitochondria; selection; single-cell

DOI:  https://doi.org/10.1073/pnas.2505704122
Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2506353122

ATP synthesis driven by atmospheric hydrogen concentrations.

Sarah Soom, Stefan Urs Moning, Gregory M Cook, James P Lingford, Ashleigh Kropp, Sieu Tran, Rhys Grinter, Chris Greening, Christoph von Ballmoos.

  All cells require a continuous supply of the universal energy currency, adenosine triphosphate (ATP), to drive countless cellular reactions. The universally conserved F1Fo-ATP synthase regenerates ATP from ADP and Pi by harnessing a transmembrane electrochemical proton gradient (pmf). Bacteria have evolved diverse pmf-forming strategies using light, organic, and inorganic energy sources. Recently, we proposed that many bacteria survive using atmospheric trace gases to produce ATP when limited for other energy sources. However, direct evidence that atmospheric energy sources are sufficient to generate pmf or drive ATP synthesis is still lacking. Here, we show that the membrane-associated hydrogen:quinone oxidoreductase Huc from Mycobacterium smegmatis can enable ATP synthesis from air. Purified Huc couples H2 oxidation to the reduction of various ubiquinone and menaquinone analogues. We designed a minimal respiratory chain in which Huc interacts with liposomes containing the nonpumping, but pmf-generating, bd-I oxidase and F1Fo-ATP synthase from Escherichia coli. Our experiments show that passive hydrogen exchange from air to solution is sufficient for the electron transfer and pmf generation required to accumulate ATP. By combining continuous culture bioenergetics measurements with theoretical calculations, we show this process is sufficient for mycobacteria to sustain pmf and ATP synthesis (two ATP molecules per H2 oxidized) for maintenance energy requirements during nutrient starvation. These findings confirm that atmospheric energy sources can be dependable 'lifeline' substrates that enable continuous energy conservation during nutrient starvation. In addition, this work provides a unique tool for ATP production in synthetic applications, which unlike other approaches is traceless without by-product accumulation.

Keywords:  ATP synthesis; aerotrophy; bioenergetics; hydrogenase; synthetic biology

DOI:  https://doi.org/10.1073/pnas.2506353122