bims-mibica 2025-01-19 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–01–19
eleven papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Reacting to reductive stress at the mitochondrial import gate.
Adenine nucleotide translocator and ATP synthase cooperate in mediating the mitochondrial permeability transition.
Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma.
Quantitative analyses of single mitochondrial components reveal an early role of small-mitochondrial-networks in priming neoplasticity.
ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling.
Imaging flow cytometry reveals divergent mitochondrial phenotypes in mitochondrial disease patients.
FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production.
Mitochondrial uncouplers inhibit oncogenic E2F1 activity and prostate cancer growth.
DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer.
Deletion of AMP-activated protein kinase impairs metastasis and is rescued by ROS scavenging or ectopic CD36 expression.
Enabling tumor-specific drug delivery by targeting the Warburg effect of cancer.

Trends Cell Biol. 2025 Jan 13. pii: S0962-8924(24)00281-2. [Epub ahead of print]

Reacting to reductive stress at the mitochondrial import gate.

Sylvie Callegari.

  A byproduct of mitochondrial energy production is the generation of reactive oxygen species (ROS). Too much ROS is toxic, but ROS deficiency is equally deleterious (reductive stress). In a recent study, McMinimy et al. uncovered a ubiquitin proteasome-mediated mechanism at the translocase of the outer membrane (TOM) complex, which senses ROS depletion and adjusts mitochondrial protein import accordingly.

Keywords:  TOM complex; mitochondrial import; proteasome; reactive oxygen species; reductive stress; ubiquitin

DOI:  https://doi.org/10.1016/j.tcb.2024.12.013
J Physiol. 2025 Jan 14.

Adenine nucleotide translocator and ATP synthase cooperate in mediating the mitochondrial permeability transition.

Ludovica Tommasin, Andrea Carrer, Federica Boscolo Nata, Elena Frigo, Federico Fogolari, Giovanna Lippe, Michela Carraro, Paolo Bernardi.

  The permeability transition (PT) is a permeability increase of the mitochondrial inner membrane causing mitochondrial swelling in response to matrix Ca2+. The PT is mediated by regulated channel(s), the PT pore(s) (PTP), which can be generated by at least two components, adenine nucleotide translocator (ANT) and ATP synthase. Whether these provide independent permeation pathways remains to be established. Here, we assessed the contribution of ANT to the PT based on the effects of the selective ANT inhibitors atractylate (ATR) and bongkrekate (BKA), which trigger and inhibit channel formation by ANT, respectively. BKA partially inhibited Ca2+-dependent PT and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT to the PT emerged at pH 6.5 (a condition that inhibits ATP synthase channel opening) in the presence of ATR, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Unexpectedly, ANT-dependent PT at pH 6.5 could also be stimulated by benzodiazepine-423 [a selective ligand of the oligomycin sensitivity conferral protein (OSCP) subunit of ATP synthase], suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. In keeping with docking simulations, ANT could be co-immunoprecipitated with ATP synthase subunits c and g, and oligomycin (which binds adjacent c subunits) decreased the association of ANT with subunit c. These results reveal a close cooperation between ANT and ATP synthase in the PT and open new perspectives in the study of this process. KEY POINTS: We have assessed the relative role of adenine nucleotide translocator (ANT) and ATP synthase in generating the mitochondrial permeability transition (PT). At pH 7.4, bongkrekate had little effect on Ca2+-dependent PT, and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT emerged at pH 6.5 (which inhibits ATP synthase channel opening) in the presence of atractylate, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Benzodiazepine-423, a selective ligand of the oligomycin sensitivity conferral protein subunit of ATP synthase, stimulated ANT-dependent PT at pH 6.5, suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. ANT could be co-immunoprecipitated with ATP synthase subunits c and g; oligomycin, which binds adjacent c subunits, decreased the association with subunit c, in keeping with docking simulations.

Keywords:  ATP synthase; adenine nucleotide translocator; calcium; mitochondria; permeability transition

DOI:  https://doi.org/10.1113/JP287147
Neuro Oncol. 2025 Jan 11. pii: noaf008. [Epub ahead of print]

Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma.

Emma Martell, Helgi Kuzmychova, Harshal Senthil, Ujala Chawla, Esha Kaul, Akaljot Grewal, Versha Banerji, Christopher M Anderson, Chitra Venugopal, Donald Miller, Tamra E Werbowetski-Ogilvie, Sheila K Singh, Tanveer Sharif.

   BACKGROUND: The mitochondrial pyruvate carrier (MPC), a central metabolic conduit linking glycolysis and mitochondrial metabolism, is instrumental in energy production. However, the role of the MPC in cancer is controversial. In particular, the importance of the MPC in glioblastoma (GBM) disease progression following standard temozolomide (TMZ) and radiation therapy (RT) remains unexplored.
METHODS: Leveraging in vitro and in vivo patient-derived models of TMZ-RT treatment in GBM, we characterize the temporal dynamics of MPC abundance and downstream metabolic consequences using state-of-the-art molecular, metabolic, and functional assays.
RESULTS: Our findings unveil a disease stage-specific role for the MPC, where in post-treatment GBM, but not therapy-naïve tumors, the MPC acts as a central metabolic regulator that suppresses differentiation. Temporal profiling reveals a dynamic metabolic rewiring where a steady increase in MPC abundance favors a shift towards enhanced mitochondrial metabolic activity across patient GBM samples. Intriguingly, while overall mitochondrial metabolism is increased, acetyl-CoA production is reduced in post-treatment GBM cells, hindering histone acetylation and silencing neural differentiation genes in an MPC-dependent manner. Finally, the therapeutic translations of these findings are highlighted by the successful pre-clinical patient-derived orthotopic xenograft (PDOX) trials utilizing a blood-brain-barrier (BBB) permeable MPC inhibitor, MSDC-0160, which augments standard TMZ-RT therapy to mitigate disease relapse and prolong animal survival.
CONCLUSION: Our findings demonstrate the critical role of the MPC in mediating GBM aggressiveness and molecular evolution following standard TMZ-RT treatment, illuminating a therapeutically-relevant metabolic vulnerability to potentially improve survival outcomes for GBM patients.

Keywords:  Glioblastoma; differentiation; metabolism; mitochondrial pyruvate carrier; tumor recurrence

DOI:  https://doi.org/10.1093/neuonc/noaf008
bioRxiv. 2025 Jan 02. pii: 2024.12.26.630414. [Epub ahead of print]

Quantitative analyses of single mitochondrial components reveal an early role of small-mitochondrial-networks in priming neoplasticity.

Mayank Saini, Swati Agarwala, Biratal Wagle, Brian Spurlock, Bharti Golchha, Danitra Parker, Kasturi Mitra.

Quantitative understanding of mitochondrial heterogeneity is necessary for elucidating the precise role of these multifaceted organelles in tumor cell development. We demonstrate an early mechanistic role of mitochondria in initiating neoplasticity by performing quantitative analyses of structure-function of single mitochondrial components coupled with single cell transcriptomics. We demonstrate that the large Hyperfused-Mitochondrial-Networks (HMNs) of keratinocytes promptly get converted to the heterogenous Small-Mitochondrial-Networks (SMNs) as the stem cell enriching dose of the model carcinogen, TCDD, depolarizes mitochondria. This happens by physical reorganization of the HMN nodes and edges, which enriches redox tuned SMNs with distinct network complexity. This leads to establishment of transcriptomic interaction between the upregulated redox relevant mtDNA genes and the lineage specific stemness gene, KRT15, prior to cell cycle exit. The SMN enrichment and related transcriptomic connections are sustained in the neoplastic cell population. Consistently, carcinogenic dose incapable of causing pronounced neoplastic stem cell enrichment fails to establish specific enrichment of SMNs and its linked mtDNA-KRT15(stemness) transcriptomic interaction prior to cell cycle exit. The mtDNA-KRT15 modulation is confirmed in cSCC tumors, while highlighting patient heterogeneity. Therefore, we propose that early enrichment of redox-tuned SMNs primes neoplastic transformation by establishing mtDNA-stemness transcriptomic interaction prior to cell cycle exit towards specifying quiescent neoplastic stem cells. Our data implies that redox-tuned SMNs, created by mitochondrial fission, would be sustained by tuning the balance of mitochondrial fission-fusion during neoplastic transformation. The proposed early role of mitochondria in cancer etiology is potentially relevant for designing precision strategies for cancer prevention and therapy.
Significance Statement: The challenges of understanding the complex role of the multifaceted and heterogenous cellular organelles, mitochondria, can be potentially overcome with their quantitative analyses. We use a combinatorial approach of quantitative analyses of single-mitochondrial-components and scRNA-seq to elucidate a mechanism of mitochondrial priming of cancer initiation by a model carcinogen. We propose that conversion of large Hyperfused-Mitochondrial-Networks (HMNs) to Small-Mitochondrial-Networks (SMNs) primes non-transformed keratinocytes towards their neoplastic transformation. Mechanistically, the SMNs, enriched by modulation of the physical nodes and edges of mitochondrial networks, tunes mitochondrial redox balance to establish transcriptomic interactions towards specifying a state of stemness. Further probing of our fundamental findings in the light of cancer heterogeneity may facilitate refinement of the various proposed mitochondria based targeted cancer therapies.

DOI: https://doi.org/10.1101/2024.12.26.630414
iScience. 2025 Jan 17. 28(1): 111544

ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling.

Kashif Shaikh, Melissa Bowman, Sarah M McCormick, Linlin Gao, Jiawen Zhang, Jesse White, John Tawil, Arun Kapoor, Ravit Arav-Boger, Christopher C Norbury, Edward W Harhaj.

  ZFAND6 is a zinc finger protein that interacts with TNF receptor-associated factor 2 (TRAF2) and polyubiquitin chains and has been linked to tumor necrosis factor (TNF) signaling. Here, we report a previously undescribed function of ZFAND6 in maintaining mitochondrial homeostasis by promoting mitophagy. Deletion of ZFAND6 in bone marrow-derived macrophages (BMDMs) upregulates reactive oxygen species (ROS) and the accumulation of damaged mitochondria due to impaired mitophagy. Consequently, mitochondrial DNA (mtDNA) is released into the cytoplasm, triggering the spontaneous expression of interferon-stimulated genes (ISGs) in a stimulator of interferon genes (STING) dependent manner, which leads to enhanced viral resistance. Mechanistically, ZFAND6 bridges a TRAF2-cIAP1 interaction and mediates the recruitment of TRAF2 to damaged mitochondria, which is required for the initiation of ubiquitin-dependent mitophagy. Our results suggest that ZFAND6 promotes the interactions of TRAF2 and cIAP1 and the clearance of damaged mitochondria by mitophagy to maintain mitochondrial homeostasis.

Keywords:  Cell biology; Omics; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.111544
iScience. 2025 Jan 17. 28(1): 111496

Imaging flow cytometry reveals divergent mitochondrial phenotypes in mitochondrial disease patients.

Irena J J Muffels, Richard Rodenburg, Hanneke L D Willemen, Désirée van Haaften-Visser, Hans Waterham, Niels Eijkelkamp, Sabine A Fuchs, Peter M van Hasselt.

  Traditional classification by clinical phenotype or oxidative phosphorylation (OXPHOS) complex deficiencies often fails to clarify complex genotype-phenotype correlations in mitochondrial disease. A multimodal functional assessment may better reveal underlying disease patterns. Using imaging flow cytometry (IFC), we evaluated mitochondrial fragmentation, swelling, membrane potential, reactive oxygen species (ROS) production, and mitochondrial mass in fibroblasts from 31 mitochondrial disease patients. Significant changes were observed in 97% of patients, forming two overarching groups with distinct responses to mitochondrial pathology. One group displayed low-to-normal membrane potential, indicating a hypometabolic state, while the other showed elevated membrane potential and swelling, suggesting a hypermetabolic state. Literature analysis linked these clusters to complex I stability defects (hypometabolic) and proton pumping activity (hypermetabolic). Thus, our IFC-based platform offers a novel approach to identify disease-specific patterns through functional responses, supporting improved diagnostic and therapeutic strategies.

Keywords:  Biological sciences; Genetics; Health sciences; Human genetics; Medicine; Natural sciences

DOI:  https://doi.org/10.1016/j.isci.2024.111496
FEBS Open Bio. 2025 Jan 16.

FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production.

Yushi Otsuka, Masato Yano.

  FAM136A deficiency has been associated with Ménière's disease. However, the underlying mechanism of action of this protein remains unclear. We hypothesized that FAM136A functions in maintaining mitochondria, even in HepG2 cells. To better characterize FAM136A function, we analyzed the cellular response caused by its depletion. FAM136A depletion induced reactive oxygen species (ROS) and reduced both mitochondrial membrane potential and ATP production. However, cleaved caspase-9 levels did not increase significantly. We next investigated why the depletion of FAM136A reduced the mitochondrial membrane potential and ATP production but did not lead to apoptosis. Depletion of FAM136A induced the mitochondrial unfolded protein response (UPRmt) and the expression levels of gluconeogenic phosphoenolpyruvate carboxykinases (PCK1 and PCK2) and ketogenic 3-hydroxy-3-methylglutaryl-CoA synthases (HMGCS1 and HMGCS2) were upregulated. Furthermore, depletion of FAM136A reduced accumulation of holocytochrome c synthase (HCCS), a FAM136A interacting enzyme that combines heme to apocytochrome c to produce holocytochrome c. Notably, the amount of heme in cytochrome c did not change significantly with FAM136A depletion, although the amount of total cytochrome c protein increased significantly. This observation suggests that greater amounts of cytochrome c remain unbound to heme in FAM136A-depleted cells.

Keywords:  ATP; FAM136A; holocytochrome c synthetase; mitochondrial membrane potential; mitochondrial stress

DOI:  https://doi.org/10.1002/2211-5463.13967
Cell Rep Med. 2024 Dec 30. pii: S2666-3791(24)00661-X. [Epub ahead of print] 101890

Mitochondrial uncouplers inhibit oncogenic E2F1 activity and prostate cancer growth.

Ohuod Hawsawi, Weinan Xue, Tingting Du, Mengqi Guo, Xiaolin Yu, Mingyi Zhang, Paul S Hoffman, Roni Bollag, Jun Li, Jia Zhou, Hongbo Wang, Junran Zhang, Zheng Fu, Xiaoguang Chen, Chunhong Yan.

  Mitochondrial uncouplers dissipate proton gradients and deplete ATP production from oxidative phosphorylation (OXPHOS). While the growth of prostate cancer depends on OXPHOS-generated ATP, the oncogenic pathway mediated by the transcription factor E2F1 is crucial for the progression of this deadly disease. Here, we report that mitochondrial uncouplers, including tizoxanide (TIZ), the active metabolite of the Food and Drug Administration (FDA)-approved anthelmintic nitazoxanide (NTZ), inhibit E2F1-mediated expression of genes involved in cell cycle progression, DNA synthesis, and lipid synthesis. Consequently, NTZ/TIZ induces S-phase kinase-associated protein 2 (SKP2)-mediated G1 arrest while impeding DNA synthesis, lipogenesis, and the growth of prostate cancer cells. The anti-cancer activity of TIZ correlates with its OXPHOS-uncoupling activity. NTZ/TIZ appears to inhibit ATP production, thereby activating the AMP-activated kinase (AMPK)-p38 pathway, leading to cyclin D1 degradation, Rb dephosphorylation, and subsequent E2F1 inhibition. Our results thus connect OXPHOS uncoupling to the inhibition of an essential oncogenic pathway, supporting repositioning NTZ and other mitochondrial uncouplers for prostate cancer therapy.

Keywords:  AMPK; E2F1; SKP2; cyclin D1; mitochondrial uncoupler; nitazoxanide; oxidative phosphorylation; p38; prostate cancer; tizoxanide

DOI:  https://doi.org/10.1016/j.xcrm.2024.101890
Cell Death Dis. 2025 Jan 14. 16(1): 16

DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer.

Xiao Hong Zhao, Man Man Han, Qian Qian Yan, Yi Meng Yue, Kaihong Ye, Yuan Yuan Zhang, Liu Teng, Liang Xu, Xiao-Jing Shi, Ting La, Yu Chen Feng, Ran Xu, Vinod K Narayana, David P De Souza, Lake-Ee Quek, Jeff Holst, Tao Liu, Mark A Baker, Rick F Thorne, Xu Dong Zhang, Lei Jin.

Mitochondrial oxidative phosphorylation (OXPHOS) is a therapeutic vulnerability in glycolysis-deficient cancers. Here we show that inhibiting OXPHOS similarly suppresses the proliferation and tumorigenicity of glycolytically competent colorectal cancer (CRC) cells in vitro and in patient-derived CRC xenografts. While the increased glycolytic activity rapidly replenished the ATP pool, it did not restore the reduced production of aspartate upon OXPHOS inhibition. This shortage in aspartate, in turn, caused nucleotide deficiencies, leading to S phase cell cycle arrest, replication fork stalling, and enrichment of the p53 pathway, manifestations of replication stress. The addition of purine nucleobases adenine and guanine along with the pyrimidine nucleoside uridine restored replication fork progression and cell proliferation, whereas the supplementation of exogenous aspartate recovered the nucleotide pool, demonstrating a causal role of the aspartate shortage in OXPHOS inhibition-induced nucleotide deficiencies and consequently replication stress and reductions in proliferation. Moreover, we demonstrate that glutamic-oxaloacetic transaminase 1 (GOT1) is critical for maintaining the minimum aspartate pool when OXPHOS is inhibited, as knockdown of GOT1 further reduced aspartate levels and rendered CRC cells more sensitive to OXPHOS inhibition both in vitro and in vivo. These results propose GOT1 targeting as a potential avenue to sensitize cancer cells to OXPHOS inhibitors, thus lowering the necessary doses to efficiently inhibit cancer growth while alleviating their adverse effects.

DOI: https://doi.org/10.1038/s41419-025-07334-4
Cell Rep. 2025 Jan 10. pii: S2211-1247(24)01534-1. [Epub ahead of print]44(1): 115183

Deletion of AMP-activated protein kinase impairs metastasis and is rescued by ROS scavenging or ectopic CD36 expression.

Gopalakrishnan Ramakrishnan, Alexander R Terry, Veronique Nogueira, Ahmed Magdy, Nissim Hay.

  AMPK's role in tumor initiation and progression is controversial. Here, we provide genetic evidence that AMPK is required for metastasis in mouse models of breast cancer. In a mouse model of spontaneous breast cancer metastasis, the deletion of AMPK before and after tumor onset decreased breast cancer metastasis, and similar results were obtained after AMPK deletion in breast cancer cell lines. The deletion of AMPK induces reactive oxygen species (ROS) levels in vitro and lipid oxidation in vivo, which likely impede metastasis. Indeed, antioxidants restore the ability of AMPK-deficient tumors to metastasize. By inhibiting acetyl-coenzyme A (CoA) carboxylases 1 and 2, AMPK maintains NADPH levels by reducing NADPH consumption in fatty acid synthesis and increasing NADPH generation via fatty acid oxidation, thus increasing the dependency on auxotrophic fatty acids. Consistently, AMPK is required for the expression of the fatty acid transporter CD36 in tumors, and ectopic expression of CD36 in AMPK-deficient cells restored their ability to metastasize.

Keywords:  AMPK; CD36; CP: Cancer; CP: Metabolism; ROS; breast cancer metastasis

DOI:  https://doi.org/10.1016/j.celrep.2024.115183
Cell Rep Med. 2025 Jan 07. pii: S2666-3791(24)00691-8. [Epub ahead of print] 101920

Enabling tumor-specific drug delivery by targeting the Warburg effect of cancer.

Jian Zhang, Tony Pan, Jimmy Lee, Sanja Goldberg, Sarah Ann King, Erting Tang, Yifei Hu, Lifeng Chen, Alex Hoover, Linyong Zhu, Oliver S Eng, Benjamin Dekel, Jun Huang, Xiaoyang Wu.

  Metabolic reprogramming of tumor cells is an emerging hallmark of cancer. Among all the changes in cancer metabolism, increased glucose uptake and the accumulation of lactate under normoxic conditions (the "Warburg effect") is a common feature of cancer cells. In this study, we develop a lactate-responsive drug delivery platform by targeting the Warburg effect. We design and test a gold/mesoporous silica Janus nanoparticle system as a gated drug carrier, in which the gold particles are functionalized with lactate oxidase and the silica particles are capped with α-cyclodextrin through surface arylboronate modification. In the presence of lactate, the lactate oxidase generates hydrogen peroxide, which induces the self-immolation reaction of arylboronate, leading to uncapping and drug release. Our results demonstrate greatly improved drug delivery specificity and therapeutic efficacy with this platform for the treatment of different cancers. Our findings present an effective approach for drug delivery by metabolic targeting of tumors.

Keywords:  Warburg effect; chemotherapy; drug delivery; immunotherapy; lactate; nanoparticle; tumor metabolism

DOI:  https://doi.org/10.1016/j.xcrm.2024.101920