bims-mibica 2025-05-04 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–05–04
twenty papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.
Understanding and Targeting Metabolic Vulnerabilities in Acute Myeloid Leukemia: An Updated Comprehensive Review.
Targeted Penetrating Motif Engineering of BH3 Mimetic: Harnessing Non-Canonical Amino Acids for Coinhibition of MCL-1 and BCL-xL in Acute Myeloid Leukemia.
Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
Targeting Melatonin to Mitochondria Mitigates Castration-Resistant Prostate Cancer by Inducing Pyroptosis.
Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
MPC2 Overexpression Drives Mitochondrial Oxidative Phosphorylation and Promotes Progression in Diffuse Large B-Cell Lymphoma.
Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.
Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
Ramping up mitochondrial DNA replication.
Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.
The mitochondrial protease ClpP is a metabolic vulnerability and an immunogenic trigger against multiple myeloma.
NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study.
T cell toxicity induced by tigecycline binding to the mitochondrial ribosome.
LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers.
Serum metabolite levels identify incipient metastatic progression of rectal cancer.
Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling.
Sirtuin 3 Protects Lung Adenocarcinoma from Ferroptosis by Deacetylating and Stabilizing Mitochondrial Glutamate Transporter Solute Carrier Family 25 Member A22.
Preclinical targeting of leukemia-initiating cells in the development future biologics for acute myeloid leukemia.

EMBO Rep. 2025 Apr 29.

Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.

Marcos Zamora-Dorta, Sara Laine-Menéndez, David Abia, Pilar González-García, Luis C López, Paula Fernández-Montes, Enrique Calvo, Jesús Vázquez, José Antonio Enríquez, Eduardo Balsa.

  Defects in mitochondrial oxidative metabolism underlie many genetic disorders with limited treatment options. The incomplete annotation of mitochondrial proteins highlights the need for a comprehensive gene inventory, particularly for Oxidative Phosphorylation (OXPHOS). To address this, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings to identify novel regulators of mitochondrial function. Our study generates a gene catalog essential for mitochondrial metabolism and maps a dynamic network of mitochondrial pathways, focusing on OXPHOS complexes. Computational analysis identifies RTN4IP1 and ECHS1 as key OXPHOS genes linked to mitochondrial diseases in humans. RTN4IP1 is found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Its deletion impairs branched-chain amino acids (BCAA) catabolism, disrupting lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.

Keywords:  CRISPR Screening; ECHS1; Mitochondria; OXPHOS; RTN4IP1

DOI:  https://doi.org/10.1038/s44319-025-00459-9
Cancers (Basel). 2025 Apr 18. pii: 1355. [Epub ahead of print]17(8):

Understanding and Targeting Metabolic Vulnerabilities in Acute Myeloid Leukemia: An Updated Comprehensive Review.

Sridevi Addanki, Lana Kim, Alexandra Stevens.

  Acute Myeloid Leukemia (AML) is characterized by aggressive proliferation and metabolic reprogramming that support its survival and resistance to therapy. This review explores the metabolic distinctions between AML cells and normal hematopoietic stem cells (HSCs), emphasizing the role of altered mitochondrial function, oxidative phosphorylation (OXPHOS), and biosynthetic pathways in leukemic progression. AML cells exhibit distinct metabolic vulnerabilities, including increased mitochondrial biogenesis, reliance on glycolysis and amino acid metabolism, and unique signaling interactions that sustain leukemic stem cells (LSCs). These dependencies provide potential therapeutic targets, as metabolic inhibitors have demonstrated efficacy in disrupting AML cell survival while sparing normal hematopoietic cells. We examine current and emerging metabolic therapies, such as inhibitors targeting glycolysis, amino acid metabolism, and lipid biosynthesis, highlighting their potential in overcoming drug resistance. However, challenges remain in translating these strategies into clinical practice due to AML's heterogeneity and adaptability. Further research into AML's metabolic plasticity and precision medicine approaches is crucial for improving treatment outcomes. Understanding and exploiting AML's metabolic vulnerabilities could pave the way for novel, more effective therapeutic strategies.

Keywords:  acute myeloid leukemia; atovoquone; azactidine; glycolysis; hematopoietic stem cells; leukemic stem cells; metabolism; oxidative phosphorylation; venetoclax

DOI:  https://doi.org/10.3390/cancers17081355
Adv Sci (Weinh). 2025 Apr 30. e2503682

Targeted Penetrating Motif Engineering of BH3 Mimetic: Harnessing Non-Canonical Amino Acids for Coinhibition of MCL-1 and BCL-xL in Acute Myeloid Leukemia.

Zhe Wang, Ruizhi Lai, Xinpei Wang, Xu Chen, Youjian Zhou, Shengbin Li, Xiaohui Qiu, Zekai Zeng, Jianye Yuan, Jinghuan Mao, Zhidong Chen, Junqing Wang.

  Acute Myeloid Leukemia (AML) remains a formidable clinical challenge, predominantly due to the emergence of resistance to existing therapeutic regimens, including BCL-2 inhibitors like Venetoclax. Here, a novel approach is introduced by engineering BH3 mimetics utilizing non-canonical amino acids (ncAAs) to achieve dual inhibition of MCL-1 and BCL-xL. Through site saturation mutagenesis scanning, the I58(Chg) mutation is identified, significantly enhancing binding affinity with IC50 values of 2.77 nm for MCL-1 and 10.69 nm for BCL-xL, reflecting an increase of fourfold or more. The developed vMIP-II-TAT-I peptide, incorporating a CXCR4-targeted penetrating motif, demonstrated superior cellular uptake, with mean fluorescence intensity (MFI) 7.2-fold higher in CXCR4-positive AML cells and exhibited a high selectivity index (SI) for AML cells, with minimal impact on normal human hematopoietic stem cells (HSCs). When combined with Venetoclax, this peptide induced synergistic apoptosis, reducing tumor burden and prolonging survival in an AML mouse model, with median survival extended to 53 days from 37 days with Venetoclax alone. These findings reveal the therapeutic potential of dual inhibition in overcoming Venetoclax resistance and selectively targeting leukemic cells with reduced off-target effects, while laying the foundation for developing advanced BH3 mimetics with enhanced targeting, binding affinity, and efficacy for AML treatment.

Keywords:  MCL‐1 & BCL‐xL inhibition; acute myeloid leukemia; drug resistance; non‐canonical amino acids; targeted penetrating peptides

DOI:  https://doi.org/10.1002/advs.202503682
Nat Metab. 2025 Apr 28.

Intracellular metabolic gradients dictate dependence on exogenous pyruvate.

Benjamin T Jackson, Angela M Montero, Sangita Chakraborty, Julia S Brunner, Paige K Arnold, Anna E Bridgeman, Pavlina K Todorova, Katrina I Paras, Lydia W S Finley.

During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.

DOI: https://doi.org/10.1038/s42255-025-01289-8
Small. 2025 Apr 26. e2408996

Targeting Melatonin to Mitochondria Mitigates Castration-Resistant Prostate Cancer by Inducing Pyroptosis.

Xiaohui Chen, Mairehaba Kadier, Mengting Shi, Kefeng Li, Hongtao Chen, Yongzhen Xia, Qiaohua Wang, Rongna Li, Yili Long, Jingbo Qin, Hao Wang, Guanmin Jiang.

  Prostate cancer frequently progresses to castration-resistant prostate cancer (CRPC) following androgen deprivation therapy, presenting a significant clinical challenge. Targeting tumor metabolism, particularly mitochondrial pathways, offers a promising strategy for overcoming CRPC. The modification of melatonin (Mel) to a triphenylphosphonium (TPP) cation-targeted mitochondria-melatonin (Mito-Mel) significantly increases its potency by over 1000-fold. Mito-Mel selectively targets mitochondria, enhancing reactive oxygen species (ROS) generation and causing mitochondrial membrane potential disruption. This leads to the inhibition of mitochondrial respiration including the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), which, in turn, suppresses CRPC survival metabolic adaptations, such as glycolysis. In vitro and in vivo experiments reveal for the first time that natural small molecule compound with mitochondrial targeting via TPP exhibits excellent anticancer efficacy by inducing tumor cellular pyroptosis and facilitating the immune response, underlining the encouraging promise of this strategy for the effective treatment of CRPC.

Keywords:  castration‐resistant prostate cancer; immune response; mito–melatonin; pyroptosis; tumor metabolism

DOI:  https://doi.org/10.1002/smll.202408996
Nat Commun. 2025 Apr 29. 16(1): 4029

Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.

Mateus Prates Mori, Oswaldo A Lozoya, Ashley M Brooks, Carl D Bortner, Cristina A Nadalutti, Birgitta Ryback, Brittany P Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky, Janine H Santos.

Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.

DOI: https://doi.org/10.1038/s41467-025-59427-5
Biochem Genet. 2025 Apr 27.

MPC2 Overexpression Drives Mitochondrial Oxidative Phosphorylation and Promotes Progression in Diffuse Large B-Cell Lymphoma.

Haoneng Wu, Qiuran Zhao, Xiaobo Ma, Ying Zhao, Qing Wang, Jinguang Bai, Songling Huang.

  Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma with heterogeneous molecular characteristics. Altered metabolism, particularly mitochondrial function, has emerged as a critical factor in cancer progression. However, the role of mitochondrial metabolism in DLBCL remains poorly understood. This study aimed to identify key mitochondrial factors associated with DLBCL progression. We analyzed transcriptomic data from multiple DLBCL datasets (GSE83632, TCGA-GTEX, GSE181063, GSE4475) using differential expression analysis, weighted gene co-expression network analysis (WGCNA), and Gene Set Enrichment Analysis (GSEA). The expression and function of the identified key factor, Mitochondrial Pyruvate Carrier 2 (MPC2), were validated using clinical samples, DLBCL cell lines, and an in vivo mouse model of xenograft. Integrative bioinformatics analysis identified MPC2 as a significantly upregulated gene in DLBCL, associated with enrichment of oxidative phosphorylation (OXPHOS) and cell cycle-related genes. MPC2 overexpression was confirmed in clinical DLBCL samples and cell lines at both mRNA and protein levels. Knockdown of MPC2 in DLBCL cells impaired mitochondrial OXPHOS, increased glycolysis, and suppressed cell proliferation, invasion, and 3D spheroid formation. In vivo, MPC2 silencing significantly reduced tumor growth in a xenograft mouse model. Our findings reveal MPC2 as a key regulator of mitochondrial function in DLBCL, promoting tumor progression through enhanced OXPHOS. This study provides new insights into the metabolic reprogramming of DLBCL and suggests MPC2 as a potential therapeutic target for this aggressive lymphoma.

Keywords:  Diffuse large B-cell lymphoma (DLBCL); Mitochondrial pyruvate carrier 2 (MPC2); Oxidative phosphorylation (OXPHOS); Transcriptomics; Tumor metabolism

DOI:  https://doi.org/10.1007/s10528-025-11100-8
Nat Metab. 2025 May 02.

Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.

Kyle M Flickinger, Carlos A Mellado Fritz, Kimberly S Huggler, Gina M Wade, Gavin R Chang, Kathryn C Fox, Judith A Simcox, Jason R Cantor.

Nicotinamide adenine dinucleotide kinase (NADK) catalyses the phosphorylation of NAD+ to produce NAD phosphate, the oxidized form of NADPH, a cofactor that serves a critical role in driving reductive metabolism. Cancer cells co-express two distinct NAD kinases that differ by localization (NADK, cytosol; NADK2, mitochondria). CRISPR screens performed across hundreds of cancer cell lines indicate that both are dispensable for growth in conventional culture media. By contrast, NADK deletion impaired cell growth in human plasma-like medium. Here we trace this conditional NADK dependence to the availability of folic acid. NADPH is the preferred cofactor of dihydrofolate reductase (DHFR), the enzyme that mediates metabolic activation of folic acid. We find that NADK is required for enabling cytosolic NADPH-driven DHFR activity sufficient to maintain folate-dependent nucleotide synthesis under low folic acid conditions. Our results reveal a basis for conditional NADK essentiality and suggest that folate availability determines whether DHFR activity can be sustained by alternative electron donors such as NADH.

DOI: https://doi.org/10.1038/s42255-025-01272-3
Dev Cell. 2025 Apr 18. pii: S1534-5807(25)00206-0. [Epub ahead of print]

Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.

Wanxin Guo, Congcong Zhang, Qianjun Zhou, Tianxiang Chen, Xin Xu, Jianfeng Zhang, Xuewen Yu, Han Wu, Xiao Zhang, Lifang Ma, Kun Qian, Daniel J Klionsky, Rui Kang, Guido Kroemer, Yongchun Yu, Daolin Tang, Jiayi Wang.

  Ferroptosis is a type of oxidative cell death, although its key metabolic processes remain incompletely understood. Here, we employ a comprehensive multiomics screening approach that identified cellular communication network factor 1 (CCN1) as a metabolic catalyst of ferroptosis. Upon ferroptosis induction, CCN1 relocates to mitochondrial complexes, facilitating electron transfer flavoprotein subunit alpha (ETFA)-dependent fatty acid β-oxidation. Compared with a traditional carnitine O-palmitoyltransferase 2 (CPT2)-ETFA pathway, the CCN1-ETFA pathway provides additional substrates for mitochondrial reactive oxygen species production, thereby stimulating ferroptosis through lipid peroxidation. A high-fat diet can enhance the anticancer efficacy of ferroptosis in lung cancer mouse models, depending on CCN1. Furthermore, primary lung cancer cells derived from patients with hypertriglyceridemia or high CCN1 expression demonstrate increased susceptibility to ferroptosis in vitro and in vivo. These findings do not only identify the metabolic role of mitochondrial CCN1 but also establish a strategy for enhancing ferroptosis-based anticancer therapies.

Keywords:  CCN1; cell death; mitochondria

DOI:  https://doi.org/10.1016/j.devcel.2025.04.004
Nat Rev Drug Discov. 2025 May 02.

Ramping up mitochondrial DNA replication.

Katie Kingwell.

DOI: https://doi.org/10.1038/d41573-025-00079-x
Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00398-5. [Epub ahead of print]44(5): 115627

Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

Jillian S Weissenrieder, Jessica Peura, Usha Paudel, Nikita Bhalerao, Natalie Weinmann, Calvin Johnson, Maximilian Wengyn, Rebecca Drager, Emma Elizabeth Furth, Karl Simin, Marcus Ruscetti, Ben Z Stanger, Anil K Rustgi, Jason R Pitarresi, J Kevin Foskett.

  Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in patients with PDAC. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced the expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGF-β. Snail re-expression and TGF-β treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.

Keywords:  CP: Cancer; CP: Metabolism; EMT; MCU; PDAC; calcium signaling; cancer; epithelial-to-mesenchymal transition; metabolism; mitochondria; pancreas; uniporter

DOI:  https://doi.org/10.1016/j.celrep.2025.115627
Blood. 2025 Apr 29. pii: blood.2024026340. [Epub ahead of print]

The mitochondrial protease ClpP is a metabolic vulnerability and an immunogenic trigger against multiple myeloma.

Tommaso Perini, Paola Zordan, Rossella Del Pizzo, Massimo Resnati, Lisa Viviani, Davide Stefanoni, Laura Cassina, Ugo Paolo Orfanelli, Matteo Trudu, Laura Oliva, Daniel Lacidogna, Mehmet K Samur, Maria Materozzi, Denise Drago, Annapaola Andolfo, Marco Patrone, Massimo Degano, Alessandra Boletta, Enrico Milan, Fabio Ciceri, Nikhil C Munshi, Matteo Bellone, Simone Cenci.

Orchestrating key homeostatic functions, mitochondria likely entail cancer vulnerabilities. Moreover, due to their bacterial ancestry they can release potent immunogenic signals. Here we show that the mitochondrial protease ClpP is both a cell-intrinsic metabolic vulnerability and an actionable immunogenic trigger in multiple myeloma (MM). We found that ClpP mRNA is higher in bone marrow (BM)-purified malignant plasma cells (PC) than in normal or premalignant counterparts and that MM lines rank first for ClpP expression among human cancers. Moreover, we demonstrated that human MM cells are highly vulnerable to ClpP inhibition in vitro and in vivo. Surprisingly, MM cell dependence on ClpP was not accounted for by its acknowledged oxidative phosphorylation surveillance activity. Proteomic discovery of proteolytic targets, metabolomics, and metabolic tracing identified a critical control exerted by ClpP on ornithine aminotransferase abundance to sustain cytosolic biosynthesis of polyamines, essential to MM cells. Transcriptomics and targeted validation also revealed activation of a cyclic GMP-AMP synthase (cGAS)-dependent type-I interferon (IFN-I) response in ClpP-silenced MM cells, whose supernatants boosted dendritic cell activation and ability to stimulate IFNg production by T cells. In vivo, ClpP silencing re-shaped the BM immune environment in immunocompetent mice, significantly expanding IFNg-producing CD4+ and CD8+ T cells and CD4+ T memory cells, while containing exhausted CD4+ T cells and myeloid derived suppressor cells. Thus, ClpP is a novel addiction of MM cells, whose inhibition not only exerts cell-intrinsic toxicity, but also triggers otherwise indolent anti-tumoral immunity. Our findings yield a novel immunogenic chemotherapeutic framework of potential relevance against myeloma.

DOI: https://doi.org/10.1182/blood.2024026340
Cell Metab. 2025 Apr 24. pii: S1550-4131(25)00212-8. [Epub ahead of print]

NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.

Sabina Chubanava, Iuliia Karavaeva, Amy M Ehrlich, Roger M Justicia, Astrid L Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N Rodrigues, Jesper F Havelund, Farina L Schlabs, Steen Larsen, Caio Y Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R Zierath, Kei Sakamoto, Thomas E Jensen, Nils J Færgeman, Gareth G Lavery, Atul S Deshmukh, Jonas T Treebak.

  Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.

Keywords:  NAD metabolism; NAD(+) biosynthesis; NAMPT; aging; epigenetic clock; exercise; mitochondrial supercomplexes; nicotinamide; reactive oxygen species; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2025.04.002
BMC Cancer. 2025 Apr 28. 25(1): 794

The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study.

Jincheng Tang, Jingting Zhang, Renyi Yang, Hongyao Chen, Xiaopeng Yu, Wei Peng, Puhua Zeng.

   BACKGROUND: Mitochondria play a multifaceted role in tumorigenesis, influencing energy metabolism, redox balance, and apoptosis. However, whether mitochondrial traits causally affect cancer risk remains unclear. This study aimed to evaluate the potential causal effects of 82 mitochondrial-related exposures on six major cancers-hepatic, colorectal, lung, esophageal, thyroid, and breast-using Mendelian randomization (MR).
METHODS: Two-sample MR analysis was performed using the inverse variance weighted (IVW) method, with MR-Egger regression and weighted median as complementary approaches. Sensitivity analyses (Cochran's Q test, MR-Egger intercept, leave-one-out) and the Steiger test were applied to assess heterogeneity, pleiotropy, and causal directionality.
RESULTS: We observed a negative correlation between "39S ribosomal protein L34, mitochondrial", and others, with hepatic cancer, while "[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial", and others exhibited a positive correlation with hepatic cancer. "Phenylalanine-tRNA ligase, mitochondrial", and others demonstrated a negative association with colorectal cancer, whereas "Methylmalonyl-CoA epimerase, mitochondrial", and others exhibited a positive correlation with colorectal cancer. "Succinate dehydrogenase assembly factor 2, mitochondrial" exhibited a negative correlation with lung cancer, while "Superoxide dismutase [Mn], mitochondrial levels" showed a positive correlation with lung cancer. "Lon protease homolog, mitochondrial" demonstrated a positive correlation with esophageal cancer. "Iron-sulfur cluster assembly enzyme ISCU, mitochondrial", and others exhibited a negative correlation with thyroid cancer, while "Diablo homolog, mitochondrial", and others showed a positive correlation with thyroid cancer. "ADP-ribose pyrophosphatase, mitochondrial", and others exhibited a negative correlation with breast cancer, while "39S ribosomal protein L34, mitochondrial", and others showed a positive correlation with breast cancer.
CONCLUSIONS: This study provides MR-based evidence that specific mitochondrial-related traits have causal effects on the risk of several common cancers. Notably, certain single-nucleotide polymorphisms (SNPs) acted as instrumental variables across multiple cancer types through shared mitochondrial mechanisms, such as oxidative stress regulation and metabolic reprogramming. These findings highlight mitochondria as cross-cutting contributors to cancer susceptibility and suggest potential avenues for mitochondrial-targeted prevention and therapy. The identification of pleiotropic genetic variants also offers insights for developing shared biomarkers and therapeutic targets across malignancies.

Keywords:  Cancers; Causal inference; Mendelian randomization; Mitochondria

DOI:  https://doi.org/10.1186/s12885-025-14201-0
Nat Commun. 2025 May 01. 16(1): 4080

T cell toxicity induced by tigecycline binding to the mitochondrial ribosome.

Qiuya Shao, Anas Khawaja, Minh Duc Nguyen, Vivek Singh, Jingdian Zhang, Yong Liu, Joel Nordin, Monika Adori, C Axel Innis, Xaquin Castro Dopico, Joanna Rorbach.

Tetracyclines are essential bacterial protein synthesis inhibitors under continual development to combat antibiotic resistance yet suffer from unwanted side effects. Mitoribosomes - responsible for generating oxidative phosphorylation (OXPHOS) subunits - share structural similarities with bacterial machinery and may suffer from cross-reactivity. Since lymphocytes rely upon OXPHOS upregulation to establish immunity, we set out to assess the impact of ribosome-targeting antibiotics on human T cells. We find tigecycline, a third-generation tetracycline, to be the most cytotoxic compound tested. In vitro, 5-10 μM tigecycline inhibits mitochondrial but not cytosolic translation, mitochondrial complex I, III and IV expression, and curtails the activation and expansion of unique T cell subsets. By cryo-EM, we find tigecycline to occupy three sites on T cell mitoribosomes. In addition to the conserved A-site found in bacteria, tigecycline also attaches to the peptidyl transferase center of the large subunit. Furthermore, a third, distinct binding site on the large subunit, aligns with helices analogous to those in bacteria, albeit lacking methylation in humans. The data provide a mechanism to explain part of the anti-inflammatory effects of these drugs and inform antibiotic design.

DOI: https://doi.org/10.1038/s41467-025-59388-9
Nat Commun. 2025 May 02. 16(1): 4112

LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers.

Chendi Li, Mohammed Usman Syed, Anahita Nimbalkar, Yi Shen, Melissa D Vieira, Cameron Fraser, Zintis Inde, Xingping Qin, Jian Ouyang, Johannes Kreuzer, Sarah E Clark, Grace Kelley, Emily M Hensley, Robert Morris, Raul Lazaro, Brian Belmonte, Audris Oh, Makeba Walcott, Christopher S Nabel, Sean Caenepeel, Anne Y Saiki, Karen Rex, J Russell Lipford, Rebecca S Heist, Jessica J Lin, Wilhelm Haas, Kristopher Sarosiek, Paul E Hughes, Aaron N Hata.

The efficacy of molecularly targeted therapies may be limited by co-occurring mutations within a tumor. Conversely, these alterations may confer collateral vulnerabilities that can be therapeutically leveraged. KRAS-mutant lung cancers are distinguished by recurrent loss of the tumor suppressor STK11/LKB1. Whether LKB1 modulates cellular responses to therapeutic stress seems unknown. Here we show that in LKB1-deficient KRAS-mutant lung cancer cells, inhibition of KRAS or its downstream effector MEK leads to hyperactivation of JNK due to loss of NUAK-mediated PP1B phosphatase activity. JNK-mediated inhibitory phosphorylation of BCL-XL rewires apoptotic dependencies, rendering LKB1-deficient cells vulnerable to MCL-1 inhibition. These results uncover an unknown role for LKB1 in regulating stress signaling and mitochondrial apoptosis independent of its tumor suppressor activity mediated by AMPK and SIK. Additionally, our study reveals a therapy-induced vulnerability in LKB1-deficient KRAS-mutant lung cancers that could be exploited as a genotype-informed strategy to improve the efficacy of KRAS-targeted therapies.

DOI: https://doi.org/10.1038/s41467-025-58753-y
Commun Med (Lond). 2025 Apr 27. 5(1): 142

Serum metabolite levels identify incipient metastatic progression of rectal cancer.

Kine M Bakke, Paula A Bousquet, Sebastian Meltzer, Tonje Bjørnetrø, Frode Rise, Alistair L Wilkins, Kathrine Røe Redalen, Anne Hansen Ree.

BACKGROUND: The cellular metabolism undergoes reprogramming during the metastatic process. We hypothesised that serum metabolites at the time of primary tumour diagnosis might identify rectal cancer patients prone to metastatic progression.
METHODS: One hundred twenty-three rectal cancer patients from a prospective observational biomarker study were followed up to 5 years after study entry. We have assessed metabolites in serum sampled at the time of diagnosis by 1H-nuclear magnetic resonance spectroscopy, using the internal reference trimethylsilylpropanoic acid for quantification.
RESULTS: Here we show that patients who develop overt metastatic disease more than 6 months after the primary tumour diagnosis have elevated serum levels (Kruskal-Wallis test) of alanine (P = 0.005), lactate (P = 0.023), pyruvate (P = 0.041) and citrate (P = 0.007) compared to those without metastases at the 5-year follow-up or with metastases already 6 months or sooner after the cancer diagnosis. Patients with serum citrate above 0.24 mmol/L have poorer progression-free survival compared to those with levels below (P < 0.001; log-rank test).
CONCLUSIONS: We observe a distinct serum metabolite profile, in particular involving citrate to the best of our knowledge shown for the first time clinically, in rectal cancer patients at heightened risk of metastasis already when the primary tumour is diagnosed, offering insights into the metabolism of metastatic progression.

DOI: https://doi.org/10.1038/s43856-025-00868-w
Cancer Res. 2025 Apr 28. OF1-OF13

Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling.

Jianqiang Yang, Fanghui Chen, Zhenzhen Fu, Fan Yang, Nabil F Saba, Yong Teng.

The tricarboxylic acid (TCA) cycle is often rewired or dysregulated to meet the increased energy and biosynthetic demands of rapidly dividing cancer cells, and targeting the TCA cycle is a potential therapeutic strategy for treating cancer. However, tumor cell metabolism can impact other cells in the tumor microenvironment, and disrupting the TCA cycle in cancer cells could impact the antitumor immune response. In this study, using CPI-613 as a model drug for TCA cycle inhibition, we identified a molecular mechanism by which blocking the TCA cycle enhances T-cell-mediated antitumor immunity in the context of head and neck squamous cell carcinoma (HNSCC). Impairment of mitochondrial metabolism by CPI-613 induced endoplasmic reticulum stress in HNSCC cells, leading to increased expression of spliced X-box-binding protein 1. This, in turn, directly suppressed the transcriptional activity of the thrombospondin-2 gene. Correspondingly, CPI-613 reduced the secretion of thrombospondin-2 from HNSCC cells, enhancing the proliferation and cytotoxic potential of tumor-infiltrating CD36+CD8+ T cells by upregulating AKT-mTOR signaling. This mechanism ultimately enhanced antitumor immunity in a syngeneic mouse model of orthotopic HNSCC following CPI-613 treatment. These findings uncover the immunomodulatory role of the TCA cycle in cancer cells and suggest that targeting it is a promising approach to harness tumor-reactive immune cells. Significance: The immunomodulatory role of the TCA cycle in cancer cells provides a therapeutic opportunity to enhance antitumor immunity by targeting tumor cell metabolism.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3477
Antioxidants (Basel). 2025 Mar 28. pii: 403. [Epub ahead of print]14(4):

Sirtuin 3 Protects Lung Adenocarcinoma from Ferroptosis by Deacetylating and Stabilizing Mitochondrial Glutamate Transporter Solute Carrier Family 25 Member A22.

Xiangyun Wei, Tiange Wang, Zhengcao Xing, Qinyun Shi, Jianmin Gu, Qiuju Fan, Hao Wang, Bin Chen, Jinke Cheng, Rong Cai.

  Solute carrier family 25 member A22 (SLC25A22) is a glutamate transporter in the inner mitochondrial membrane that is known to suppress ferroptosis in pancreatic ductal adenocarcinoma (PDAC). Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase, and we previously demonstrated that targeting SIRT3 sensitized glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11. The purpose of this study was to analyze the effect of SIRT3-mediated deacetylation of mitochondrial SLC25A22 on RAS-selective lethal 3 (RSL3)-induced ferroptosis in lung adenocarcinoma (LUAD). We found that the expression of SLC25A22 and SIRT3 had a high positive correlation and that their expression was greater in LUAD tissues than in adjacent tissues. The RSL3-induced ferroptosis of LUAD led to upregulation of SLC25A22 and SIRT3, and SIRT3 protected RSL3-induced LUAD from ferroptosis in vitro and in vivo. At the molecular level, SIRT3 bound with SLC25A22 and deacetylated this protein. Targeting SIRT3 enhanced the acetylation of SLC25A22, decreased its ubiquitination, and promoted 26S proteasome degradation in LUAD cells. Therefore, our results demonstrated that SIRT3 protected LUAD cells from RSL3-induced ferroptosis, and this effect is at least partially due to its deacetylation of SLC25A22, revealing that the SIRT3-SLC25A22 axis has an important role in regulating the ferroptosis of LUAD cells.

Keywords:  Sirtuin 3; ferroptosis; lung adenocarcinoma; solute carrier family 25 member 22

DOI:  https://doi.org/10.3390/antiox14040403
Expert Opin Ther Targets. 2025 Apr 30.

Preclinical targeting of leukemia-initiating cells in the development future biologics for acute myeloid leukemia.

Jiaxin Dong, Marina Konopleva.

   INTRODUCTION: Leukemia-initiating cells (LICs) are a critical subset of cells driving acute myeloid leukemia (AML) relapse and resistance to therapy. They possess unique properties, including metabolic, epigenetic, and microenvironmental dependencies, making them promising therapeutic targets.
AREAS COVERED: This review summarizes preclinical advances in targeting AML LICs, including strategies to exploit metabolic vulnerabilities, such as the reliance on oxidative phosphorylation (OXPHOS), through the use of mitochondrial inhibitors; target epigenetic regulators like DOT1L (Disruptor of Telomeric Silencing 1-like) to disrupt LIC survival mechanisms; develop immunotherapies, including CAR (chimeric antigen receptor) T-cell therapy, and bispecific antibodies; and disrupt LIC interactions with the bone marrow microenvironment by inhibiting supportive niches.
EXPERT OPINION: LIC-targeted therapies hold significant promise for revolutionizing AML treatment by reducing relapse rates and improving long-term outcomes. However, challenges such as LIC heterogeneity, therapy resistance, and associated toxicity persist. Recent studies have illuminated the distinct biological characteristics of LICs, advancing our understanding of their behavior and vulnerabilities. These insights offer new opportunities to target LICs at earlier disease stages and to explore combination therapies with other targeted treatments, ultimately enhancing therapeutic efficacy and improving patient outcomes.

Keywords:  Immunotherapy; Leukemia-initiating cells; acute myeloid leukemia; bone marrow microenvironment; epigenetic regulation; metabolic vulnerabilities

DOI:  https://doi.org/10.1080/14728222.2025.2500417