bims-mibica 2026-04-19 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–04–19
thirteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia.
Mitochondrial translocation of MDM2 and TFAM reprograms metabolism in treatment-refractory cancers.
SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity.
Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
Copper Transporter 1‑Mediated Deregulation of Copper Homeostasis Impacts MYC and Oxidative Phosphorylation Pathways and Increases the Sensitivity of Tumor Cells to Complex I Inhibitors.
The microprotein SMIM26 connects metabolite transporters of the outer and inner mitochondrial membranes and is essential for respiratory chain function.
Proteome profiles of esophageal squamous cell carcinoma tie mitochondrial complex I to immunotherapy.
Mitochondrial superoxide sustains a senescence-like phenotype in PARP- inhibited ovarian cancer cells by stabilizing HIF1α.
SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.
Cytochrome c as a central regulator of mitochondrial function in cancer metabolism.
Targeting BCL-2 and PI3K signaling pathways enhances cytotoxicity of gemtuzumab ozogamicin against acute myeloid leukemia cells.
Tolerance to extracellular acidic pH facilitates tumor plasticity.
Mitochondrial DNA copy number in leukocytes predicts long-term survival in prostate cancer.

Blood Neoplasia. 2026 May;3(2): 100196

Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia.

Johnson Ung, Su-Fern Tan, Jeremy J P Shaw, Maansi Taori, Tess M Deddens, Giovana Venancio, McLane M Montgomery, James T Hagen, Raphael T Aruleba, Upendar R Golla, Arati Sharma, B Bishal Paudel, Irene Lee, Bhavishya Ramamoorthy, Kevin A Janes, Francine Garrett-Bakelman, Myles C Cabot, Kelsey H Fisher-Wellman, Todd E Fox, David F Claxton, Charles E Chalfant, David J Feith, Thomas P Loughran.

Resistance to combination regimens containing the B-cell lymphoma 2 (BCL-2) inhibitor and BH3 mimetic venetoclax in acute myeloid leukemia (AML) is a growing clinical challenge for this extensively used agent. We previously established the antileukemic properties of ceramide, a tumor-suppressive sphingolipid, in AML, and demonstrated that upregulated expression of acid ceramidase (AC), a ceramide-neutralizing enzyme, supports leukemic survival and resistance to BH3 mimetics. Here, we report the antileukemic efficacy and mechanisms of cotargeting AC and BCL-2 in venetoclax-resistant AML. Analysis of the BeatAML data set revealed a positive relationship between increased AC gene expression and venetoclax resistance. Pharmacologic AC inhibition with the ceramide analog SACLAC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. SACLAC + venetoclax was synergistically lethal when evaluated ex vivo across a cohort of venetoclax-resistant (n = 21) and venetoclax-sensitive (n = 46) primary samples from patients with AML. Moreover, the SACLAC + venetoclax combination was equipotent to the combination of venetoclax + cytarabine at reducing cell viability across primary patient samples. Mechanistically, cotargeting AC and BCL-2 increased ceramide to levels that trigger a cytotoxic integrated stress response (ISR), ISR-mediated NOXA protein upregulation, mitochondrial dysregulation, and caspase-dependent cell death. Importantly, AC knockdown sensitized AML cells to venetoclax and induced NOXA protein accumulation, whereas NOXA knockdown protected against AC and BCL-2 cotargeting. Collectively, these findings demonstrate the efficacy of cotargeting AC and BCL-2, and rationalize targeting AC as a therapeutic approach for venetoclax-sensitive and -resistant AML.

DOI: https://doi.org/10.1016/j.bneo.2026.100196
NPJ Precis Oncol. 2026 Apr 16.

Mitochondrial translocation of MDM2 and TFAM reprograms metabolism in treatment-refractory cancers.

Jie Qing Eu, Nur Afiqah Binte Mohamed Salleh, Jayshree Hirpara, Naoto Ohi, Emiri Omori Takaki, Tuan Zea Tan, Ju Ee Seet, Susan Swee-Shan Hue, Shu Jun Chan, Dorothy Xi Yue Lim, Lingzhi Wang, Regina Tong Xin Wong, Azhar Ali, Yaw Chyn Lim, Boon-Cher Goh, Li Ren Kong, Shazib Pervaiz, Andrea LA Wong.

Tyrosine kinase inhibitors (TKI) are frontline therapies for oncogene-addicted cancers, yet metabolic rewiring frequently drives acquired resistance. Here, we identify a mitochondrial trafficking mechanism that regulates oxidative phosphorylation (OXPHOS) dependence in TKI-resistant tumours. Using resistant cell models and patient-derived materials, we demonstrate that OXPHOS activation is regulated by an AKT-driven, competitive interaction between mitochondrial MDM2 and the mitochondrial transcription factor TFAM at mitochondrial DNA (mtDNA). Mechanistically, adaptive AKT activation promotes cytosolic redistribution of MDM2 with reciprocal accumulation of TFAM in mitochondrial, enhancing mtDNA transcription and OXPHOS activity. To validate this mitochondrial-cytosolic exchange, we develop a quantitative, high-resolution imaging approach to map MDM2 and TFAM localization. In a TKI-resistant clinical cohort (n = 76), we revealed a positive correlation between AKT activation, MDM2 phosphorylation and TFAM mitochondrial trafficking, defining a spatial, subcellular biomarker signature of metabolically reprogrammed TKI resistance. Pharmacologic disruption of the AKT-MDM2-TFAM signaling axis reverse TKI resistance, linking mitochondrial genome regulation to therapy resistance and suggesting a metabolic vulnerability for combinatorial targeting.

DOI: https://doi.org/10.1038/s41698-025-01257-1
bioRxiv. 2026 Apr 07. pii: 2026.04.03.716311. [Epub ahead of print]

SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity.

Dingcheng Sun, Guangrui Ding, Haonan Lin, Guo Chen, Chun-Chin Wang, Seema Bachoo, Sarah E Bohndiek, Ji-Xin Cheng.

Mitochondria, acting as the energy powerhouse, biosynthetic center, and reductive equivalent hub of the cell, participate in cellular metabolic activities. However directly imaging mitochondrial chemical content and quantifying metabolic activity in living cells remain challenging. Here, by Self-PErmutation Noise2noise Denoiser enhanced Hyperspectral Stimulated Raman Scattering (SPEND-hSRS) microscopy, we demonstrate fingerprint-region metabolic imaging of fumarate, a key intermediate in the tricarboxylic acid (TCA) cycle, with sub-millimolar sensitivity. In chemotherapy-stressed bladder cancer cells, fumarate imaging revealed two mitochondrial subpopulations with divergent TCA metabolic preferences quantified by ratio metric analysis. Pixel-wise least absolute shrinkage and selection operator (LASSO) spectral unmixing further reconstructs fumarate and lipid maps, uncovering localized fumarate enrichment in protrusions. Extending to CH-window hyperspectral SRS imaging, we uncover the interplay between mitochondria and lipid droplets (LDs) in protrusions, where fatty acid is found to be released from LDs, to fuel the TCA cycle. Together, our work establishes SPEND-hSRS as high-resolution platform for linking fumarate to mitochondrial heterogeneity. Our results provide new insights into how mitochondrial heterogeneity and interaction with LDs drive cancer cell adaptation to stress.

DOI: https://doi.org/10.64898/2026.04.03.716311
Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00193-0. [Epub ahead of print]86(8): 1511-1528.e12

Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.

Lvxin Xie, Shuchao Ren, Li Zhang, Ziqing Wang, Tong Wu, Qing Dai, Shikun Xiang, Zhihua Qian, Yufan Xian, Shutong Xu, Xiao-Lin Chen, Chuan He, Yi Liu, Zhipeng Zhou.

  Mitochondria generate ATP through oxidative phosphorylation (OXPHOS), with core structural subunits encoded by mitochondrial DNA (mtDNA) and translated by mitochondrial ribosomes. However, how mitochondrial translation elongation influences OXPHOS biogenesis remains unclear. Here, we show that in Neurospora crassa, the mitochondrial ribosomal RNA (rRNA) methyltransferase 1 (MRM1) promotes OXPHOS biogenesis by repressing translation elongation independently of its catalytic activity. The N-terminal intrinsically disordered region (IDR) of MRM1 binds simultaneously to mitochondrial ribosomes and mRNAs. Disrupting either interaction accelerates elongation and enhances synthesis of mtDNA-encoded OXPHOS subunits but impairs their co-translational folding and membrane insertion. Pharmacological slowing of mitochondrial translation partially alleviates these defects. The MRM1 IDR is conserved in Ascomycete fungi and is essential for plant infection by Magnaporthe oryzae. Together, our findings identify translation elongation control as a mechanism coordinating mitochondrial protein synthesis and folding during OXPHOS biogenesis and MRM1 as a potential target for broad-spectrum antifungal strategies.

Keywords:  Magnaporthe oryzae; Neurospora crassa; mitochondrial rRNA methyltransferase; mitochondrial translation; oxidative phosphorylation; protein folding; translation elongation

DOI:  https://doi.org/10.1016/j.molcel.2026.03.017
ACS Pharmacol Transl Sci. 2026 Apr 10. 9(4): 902-924

Copper Transporter 1‑Mediated Deregulation of Copper Homeostasis Impacts MYC and Oxidative Phosphorylation Pathways and Increases the Sensitivity of Tumor Cells to Complex I Inhibitors.

Rima Mouawad, Nada H Eisa, Andrii Balia, Joyeeta Roy, Nouri Neamati.

  Certain tumors are dependent on copper for proliferation, metastasis, and energy production, making them particularly susceptible to copper depletion. Altering copper homeostasis has emerged as a promising strategy for treating these cancers. Previously, we synthesized novel compounds, JR4-187 (JR4) and JR5-26B (JR5), which demonstrated copper-dependent in vivo efficacy. RNA-seq analysis revealed that JR4 treatment in colon cancer cells leads to a marked downregulation of oxidative phosphorylation and MYC-targeted genes. Both JR4 and JR5 reduce MYC and NDUFS7 protein levels. Additionally, JR4 and JR5 increase tumor cell sensitivity to complex I inhibitors, including AGB-374, a novel NDUFS7 inhibitor that we developed. AGB-374 exhibited in vivo efficacy when administered orally, both as a single agent and in combination with JR5, in a mouse model of colon cancer. Our findings indicate a significant functional relationship between CTR1 and NDUFS7, providing a foundation for the development of new cancer therapies.

Keywords:  CTR1; MYC; NDUFS7; OXPHOS; SLC31A1; copper chelation

DOI:  https://doi.org/10.1021/acsptsci.5c00651
Genes Dev. 2026 Apr 16.

The microprotein SMIM26 connects metabolite transporters of the outer and inner mitochondrial membranes and is essential for respiratory chain function.

Kevin Heizler, Anastasia Chugunova, Mara Hofmann, Michaela Prochazkova, Jan Procházka, Hung Ho-Xuan, Joerg Fallmann, Karel Stejskal, Gabriela Krssakova, Stefanie Bader, Erman Kocak, Dogukan Yasar, Patricia Luckner, Gerhard Lehmann, Julian Köngeter, Marisa Riester, Elisabeth Roitinger, Christian Wetzel, Sven Diederichs, Radislav Sedlacek, Astrid Bruckmann, J Christof M Gebhardt, Andrea Pauli, Gunter Meister.

  Microproteins represent a class of short polypeptides with very diverse cellular functions. Microproteins frequently escape proteomics-based identification, making the extent and potential functions of small proteins largely elusive. Some microproteins originate from transcripts that are annotated as long noncoding RNAs (lncRNAs). Here, we functionally characterize SMIM26, a microprotein localized to mitochondria. In biochemical and single-molecule tracking studies, we found that SMIM26 interacts with VDAC1/2 in the outer mitochondrial membrane and with SLC25A6 in the inner mitochondrial membrane. It spans the intermembrane space and is phosphorylated at distinct residues. Knockout cells are viable, but respiratory chain activity is strongly reduced. Interestingly, knockout mice are not viable and die at early developmental stages. Zebrafish homozygous smim26 mutants are viable but show reduced fitness and survival compared with their wild-type or heterozygous siblings. Consistent with the mitochondrial phenotype in cell lines, respiration is also reduced in homozygous zebrafish embryos. Our work suggests that SMIM26 coordinates metabolite transport through the inner and outer mitochondrial membranes and is essential for respiratory chain function in vivo.

Keywords:  SMIM26; metabolite transport; microprotein; mitochondria; respiratory chain

DOI:  https://doi.org/10.1101/gad.353272.125
EMBO Mol Med. 2026 Apr 11.

Proteome profiles of esophageal squamous cell carcinoma tie mitochondrial complex I to immunotherapy.

Fahan Ma, Yan Li, Chan Xiang, Bing Wang, Jie Lv, Zhanxian Shang, Weiguang Zhang, Zhaoyu Qin, Yan Pu, Kai Li, Jinzhi Wei, Su-Bei Tan, Jinwen Feng, Haohua Teng, Peipei Zhang, Jiaying Deng, Yunzhi Wang, Chao Zhang, Sha Tian, Guichao Li, Mingqiang Kang, Changsheng Du, Yuchen Han, Chen Ding.

Immunotherapy has revolutionized cancer treatment, yet many patients show non-sensitivity. Here, we collected treatment-naïve samples from 190 esophageal squamous cell carcinoma (ESCC) patients undergoing anti-programmed death 1 (PD1) immunotherapy for proteome, phosphoproteome, and immunohistochemistry (IHC) analysis. Proteome-based stratification of ESCC identifies three proteomic subtypes (G-I-G-III) related to immunotherapy response and different molecular features, revealing that patients with high mitochondrial complex I protein expression show sensitivity to anti-PD1 immunotherapy. High mitochondrial complex I protein expression of ESCC cells or patient-derived organoids increases sensitivity to CD8 + T cell-mediated killing in the co-culture systems. Phosphoproteomic data analysis reveals YAP1 activation impairs immunotherapy efficacy. Inhibiting YAP1 or increasing mitochondrial complex I levels bolsters immunotherapy effectiveness in ESCC allograft tumors. Finally, we develop a highly accurate predictive model (AUC ≥ 0.90) by the signatures of mitochondrial complex I-mediated anti-tumor immune response and validate it in independent cohorts. This study provides a rich resource for investigating the mechanisms and indicators of immunotherapy in ESCC.

DOI: https://doi.org/10.1038/s44321-026-00413-9
Redox Biol. 2026 Apr 07. pii: S2213-2317(26)00156-4. [Epub ahead of print]93 104158

Mitochondrial superoxide sustains a senescence-like phenotype in PARP- inhibited ovarian cancer cells by stabilizing HIF1α.

Tingting Yang, Wenqing Bu, Xiaotong Xue, Xuemin Wu, Yipeng Zhou, Yue Chen, Yanan Li, Jia Zhang, Peishan Li, Fangrong Shen, Yufang Shi, Changshun Shao.

  Ovarian cancer is the deadliest gynecological malignant tumor and is known as the "silent killer". PARP inhibitors are being increasingly used for their excellent efficacy in the treatment of ovarian cancer. While PARP inhibitors are known to interfere with DNA repair and cause DNA damage, the fates of cancer cells and associated metabolic features in response to PARP inhibition are not well characterized. We herein show that ovarian cancer cells treated with PARP inhibitors exhibit a senescence-like phenotype that is characterized by cell cycle arrest, positive staining of senescence-associated β-gal, and increased accumulation of dysfunctional mitochondria. The survival of senescence-like cells is sustained by glycolysis that is driven by an augmented axis of mitochondrial reactive oxygen species (mtROS) and HIF1α. Mitochondrial antioxidant, inhibition of HIF1α activation and restriction of glycolysis can each block the entry into and the sustenance of the senescence-like state in PARP-inhibited ovarian cancer cells. The senescence-like phenotype, HIF1α activation and lactate production were attenuated in tumor xenografts co-treated with PARP inhibitor Rucaparib and mitochondrial antioxidant. The metabolic reliance on mtROS-driven glycolysis in ovarian cancer cells treated with PARP inhibitors has implications in cancer treatment.

Keywords:  Glycolysis; HIF1α; Mitochondrial ROS; Ovarian cancer; PARP inhibitors; Senescence

DOI:  https://doi.org/10.1016/j.redox.2026.104158
Nat Cell Biol. 2026 Apr 17.

SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.

Shanshan Liu, Mark Gad, Caifan Li, Kevin Cho, Yuyang Liu, Khando Wangdu, Viktor Belay, Alon Millet, Hiroyuki Kojima, Henry Sanford, Michele Wölk, Linas Urnavicius, Maria Fedorova, Gary J Patti, Ekaterina V Vinogradova, Richard K Hite, Kıvanç Birsoy.

The endoplasmic reticulum (ER) requires an oxidative environment to support the efficient maturation of secretory and membrane proteins. This is in part established by glutathione, a redox-active metabolite present in reduced (GSH) and oxidized (GSSG) forms. The ER maintains a higher GSSG:GSH ratio than the cytosol; however, the mechanisms controlling ER redox balance remain poorly understood. To address this, we developed a method for the rapid immunopurification of the ER, enabling comprehensive profiling of its proteome and metabolome. Combining this approach with CRISPR screening, we identified SLC33A1 as the major ER GSSG exporter in mammalian cells. Loss of SLC33A1 led to GSSG accumulation in the ER and a liposome-based assay demonstrated that SLC33A1 directly transports GSSG. Cryogenic electron microscopy structures and molecular dynamics simulations revealed how SLC33A1 binds GSSG and identified residues critical for its transport. Finally, an imbalance in GSSG:GSH ratio induced ER stress and dependency on the ER-associated degradation pathway, driven by a shift in protein disulfide isomerases towards their oxidized forms. Together, our work establishes SLC33A1-mediated GSSG export as a key mechanism for ER redox homeostasis and protein maturation.

DOI: https://doi.org/10.1038/s41556-026-01922-y
Discov Oncol. 2026 Apr 13.

Cytochrome c as a central regulator of mitochondrial function in cancer metabolism.

Aisha Shabir, Shazia Sofi, Nusrat Jan, Burhan Ul Haq, Hina Qayoom, Manzoor A Mir.

  Cytochrome c (Cytc) becomes a crucial regulator, determining the fate of cells at the confluence of apoptosis and metabolism. From its primary origin as an electron transporter in the mitochondrial electron transport chain (ETC), Cytc has ascended to a crucial role in apoptosis, triggering cascades of cellular deathupon liberation from the mitochondria.The intricate interplay between Cytc and apoptosis protease-activating factor-1 (Apaf-1) culminates in the apoptosome formation and activation of the cascade of caspase, underscoring the significance of Cytc in regulating cell death pathways. Moreover, tale of Cytc is adorned with post-translational modifications, particularly phosphorylation, which fine-tune its functions in respiration and apoptosis, adding layers of complexity to its regulatory effectiveness. Cytc becomes a lighthouse in the intricate web of cancer, its expression patterns providing hints about prognosis and paths toward treatment. Nevertheless, the story becomes more complex as Cytc becomes entangled in the metabolic reprogramming of cancer cells, implying a crucial involvement in tumor progression and treatment resistance. Collectively, these findings highlight Cytc as a multifunctional regulator of cellular fate that integrates mitochondrial respiration, apoptotic signalling, and metabolic reprogramming, suggesting new opportunities for cancer diagnosis and therapeutic intervention. Even if progress has been made, the story of Cytc is far from over, demanding more investigation into its complexities and biological consequences related to cancer. It represents a therapeutic target in the fight against cancer considering its substantial role in tumor metabolism. It promises a future in which creative solutions to the challenges of cellular destiny will be found. In this review, we have tried to highlight the multidimensional realm of Cytc, connecting threads between apoptosis, metabolic reprogramming, and the Warburg effect in line with cancer.

Keywords:  Apoptosis; Cytochrome c; Electron transport chain; Metabolic reprogramming; Mitochondrial outer membrane permeability; Warburg effect

DOI:  https://doi.org/10.1007/s12672-026-05014-z
Biochem Biophys Res Commun. 2026 Apr 09. pii: S0006-291X(26)00516-4. [Epub ahead of print]817 153752

Targeting BCL-2 and PI3K signaling pathways enhances cytotoxicity of gemtuzumab ozogamicin against acute myeloid leukemia cells.

Malgorzata Opydo, Malgorzata Wojtaszek, Aleksandra Mosurek, Gabriela Burczyk, Anna Such, Elzbieta Kolaczkowska.

  Gemtuzumab ozogamicin (GO) is a humanized IgG4 anti-CD33 monoclonal antibody conjugated to the cytotoxic derivative of calicheamicin. GO was the first antibody-drug conjugate (ADC) approved for the treatment of patients with CD33+ acute myeloid leukemia (AML). Although GO exhibits cytotoxic activity against AML cells, its effectiveness may be limited by resistance mechanisms, highlighting the need to develop strategies that increase cell sensitivity to this ADC. In this study, we investigated whether inhibition of the anti-apoptotic protein BCL-2 and/or phosphatidylinositol 3 kinase (PI3K) pathway enhances GO-mediated cytotoxicity in AML cells with distinct phenotypes. Expectedly, GO decreased cell viability, induced G2/M arrest and apoptosis in leukemic cells. However, the degree of cellular response to GO differed among the four AML cell lines studied, indicating existence of resistant and sensitive cells, and this effect did not correlate with CD33 expression. We report that selective inhibition of BCL-2 and/or PI3K enhanced the pro-apoptotic effect of GO, both in GO-sensitive and GO-resistant AML cell lines. Importantly, the most pronounced effects were observed with the triple combination treatment, which successfully overcame GO resistance. Such inhibition caused cell line-dependent changes in the expression of apoptotic regulators, including BCL-2, MCL-1 and p53 protein, suggesting that cellular context shapes responses to combined treatments. In conclusion, our findings identify BCL-2 and PI3K inhibition as a promising new approach to sensitize AML cells to GO therapy, and highlight the importance of these pathways in determining the cellular response to gemtuzumab ozogamicin.

Keywords:  ABT-199; Acute myeloid leukemia; BCL-2; PI3K/AKT signaling pathway; gemtuzumab ozogamicin

DOI:  https://doi.org/10.1016/j.bbrc.2026.153752
Cell Rep. 2026 Apr 16. pii: S2211-1247(26)00304-9. [Epub ahead of print] 117226

Tolerance to extracellular acidic pH facilitates tumor plasticity.

Manami Hasegawa, Bo Xu, Keisuke Maeda, Motoaki Seki, FeiFei Cai, Runmei Cui, Ritsuko Ando, Suzuka Nakagawa, Ayana Sakamoto, Cayla Boycott, Hiroyuki Yatabe, Miyuki Nishida, Ken Matsumoto, Chisato Iwabuchi-Yoshida, Sho Aki, Kazuyuki Yamagata, Rika Tsuchida, Mami Takahashi, Futoshi Kuribayashi, Hiroyasu Kidoya, Hiroshi Hirata, Shingo Matsumoto, Shinsuke Sando, Hideyuki Yanai, Nozomu Yachie, Tsuyoshi Osawa.

  Cancer cells sustain glycolysis despite oxygen availability, creating an acidic microenvironment via proton and lactate export, but how they survive acid stress is unclear. We show that severe acidification (pH 5.6) induces necroptosis, whereas moderate acidity (pH 6.8) prevents death and enables anchorage-independent survival and tumor initiation. RNA sequencing of suspended cells at pH 6.8 revealed activation of respiratory chain complex and complement pathways, consistent with adaptation to this pH. A genome-wide CRISPR-Cas9 knockout screen in PANC1 cells under chronic acidity identified FAM129C as a regulator of acid tolerance and survival. In xenografts, FAM129C overexpression reduced PIGR expression, implicating this axis in tumor growth and immune infiltration. Anti-PD-L1 plus a complement inhibitor showed synergistic anti-tumor activity in PIGR-overexpressing tumors. Thus, acidic stress engages a pathway that allows cancer cells to evade necroptosis and promote tumor plasticity, providing potential avenues for therapeutic intervention targeting pH-dependent cell-death pathways.

Keywords:  CP: cancer; CP: immunology; acidosis; cancer metabolism; complement pathway; epithelial-mesenchymal transition; extracellular acidic pH; immune checkpoints; immune tolerance; necroptosis; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2026.117226
Clin Chem Lab Med. 2026 Apr 16.

Mitochondrial DNA copy number in leukocytes predicts long-term survival in prostate cancer.

Tanja Langsenlehner, Katarzyna Paal, Eva-Maria Thurner, Mirjam Langmüller, Renate Sternat, Wilfried Renner.

   OBJECTIVES: Low mitochondrial DNA copy number (mtCN) in leukocytes is a predictor of all-cause mortality, independent of age and sex. For malignant diseases, results about the prognostic value of leukocyte mtCN have been conflicting. Aim of the present study was to analyze the prognostic value of mtCN for long-term prostate cancer survival.
METHODS: Blood samples of prostate cancer patients were obtained before initiation of radiotherapy. Relative mtCN was determined by a quantitative polymerase chain reaction method in 662 patients with prostate cancer. Main outcome was overall survival.
RESULTS: During a follow-up time of 120 months, 218 (32.9 %) patients died. In a univariate Cox regression analysis, higher mtCN z-score was significantly associated with lower overall mortality (hazard ratio 0.83, 95 % confidence interval 0.72-0.96; p=0.009). In a multivariate Cox regression model including age at diagnosis, androgen deprivation therapy, and risk group (based on PSA level, GS, and T stage), higher mtCN z-score remained a significant predictor of lower overall mortality (hazard ratio 0.85, 95 % confidence interval 0.74-0.98; p=0.029).
CONCLUSIONS: High leukocyte mtCN predicts better overall survival in patients with prostate cancer.

Keywords:  mitochondria; prostate cancer; survival

DOI:  https://doi.org/10.1515/cclm-2025-1464