bims-midysc 2025-01-05 papers

bims-midysc

Biomed News

on Mitochondria dysfunction in cancer

Issue of 2025–01–05
nine papers selected by
Papachristodoulou Lab

Advances in ferroptosis for castration-resistant prostate cancer treatment: novel drug targets and combination therapy strategies.
Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis.
The Warburg Effect: Is it Always an Enemy?
Metabolic plasticity in pancreatic cancer: The mitochondrial connection.
A new peptide inhibitor of C1QBP exhibits potent anti-tumour activity against triple negative breast cancer by impairing mitochondrial function and suppressing homologous recombination repair.
Demethylzeylasteral inhibits oxidative phosphorylation complex biogenesis by targeting LRPPRC in lung cancer.
The relationship between mitochondrial health, telomerase activity and longitudinal telomere attrition, considering the role of chronic stress.
Imaging phenotype reveals that disulfirams induce protein insolubility in the mitochondrial matrix.
Aging-induced changes in lymphatic muscle cell transcriptomes are associated with reduced pumping of peripheral collecting lymphatic vessels in mice.

Prostate Cancer Prostatic Dis. 2024 Dec 28.

Advances in ferroptosis for castration-resistant prostate cancer treatment: novel drug targets and combination therapy strategies.

Huizhu Chen, Feng Lyu, Xianshu Gao.

BACKGROUND: Metastatic prostate cancer (PCa) has much lower survival and ultimately develops castration resistance, which expects novel targets and therapeutic approaches. As a result of iron-dependent lipid peroxidation, ferroptosis triggers programmed cell death and has been associated with castration-resistant prostate cancer (CRPC).
SUBJECTS: To better understand how ferroptosis can be used to treat CRPC, we reviewed the following: First, ferroptosis mechanisms and characteristics. We then pay attention to ferroptosis effects on CRPC, and the relationship between ferroptosis and CRPC treatment. Finally, we'd like to figure out if ferroptosis could predict the prognosis of CRPC thus screening early for populations that may benefit from appropriate therapies.
RESULTS: The review demonstrated that ferroptosis regulators like PI3K/AKT/mTOR, DECR1 et al., have a significant role in the development of CRPC and that several inducers of ferroptosis, such as erastin, BSO, RSL3, and FIN56, have already demonstrated their effects in that area. What's more, ferroptosis is crucial for radiation-induced anticancer effects by inducing lipid peroxidation and regulating p53, AMPK, and others. Additionally, it has been discovered that certain GPX4 and SLC7A11 inhibitors can increase radiosensitivity, which brings new combination strategies. Finally, among the genes associated with ferroptosis, which may be excellent predictors of prostate cancer prognosis, several risk models have been developed and shown promising predictive capabilities.
CONCLUSIONS: Ferroptosis can serve as a potential therapeutic target for CRPC, and could be a new strategy for combination therapy. Moreover, ferroptosis-related genes may be great indicators of PCa prognosis. Further research on ferroptosis in CRPC therapy can benefit from the frameworks provided by this review.

DOI: https://doi.org/10.1038/s41391-024-00933-w
Sci Adv. 2025 Jan 03. 11(1): eads8489

Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis.

Xiujie Li-Harms, Jingjun Lu, Yu Fukuda, John Lynch, Aditya Sheth, Gautam Pareek, Marcin M Kaminski, Hailey S Ross, Christopher W Wright, Amber L Smith, Huiyun Wu, Yong-Dong Wang, Marc Valentine, Geoffrey Neale, Peter Vogel, Stanley Pounds, John D Schuetz, Min Ni, Mondira Kundu.

The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorly characterized. To determine the impact of somatic mtDNA mutations on this process, we assessed the leukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A) with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesis in recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemia in those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygous and homozygous HPCs caused similar baseline impairments in mitochondrial function, only heterozygous HPCs responded to and supported altered metabolic demands associated with NMyc overexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenase inhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growth of NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenase kinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity in leukemogenesis.

DOI: https://doi.org/10.1126/sciadv.ads8489
Front Biosci (Landmark Ed). 2024 Nov 27. 29(12): 402

The Warburg Effect: Is it Always an Enemy?

Christos Papaneophytou.

  The Warburg effect, also known as 'aerobic' glycolysis, describes the preference of cancer cells to favor glycolysis over oxidative phosphorylation for energy (adenosine triphosphate-ATP) production, despite having high amounts of oxygen and fully active mitochondria, a phenomenon first identified by Otto Warburg. This metabolic pathway is traditionally viewed as a hallmark of cancer, supporting rapid growth and proliferation by supplying energy and biosynthetic precursors. However, emerging research indicates that the Warburg effect is not just a strategy for cancer cells to proliferate at higher rates compared to normal cells; thus, it should not be considered an 'enemy' since it also plays complex roles in normal cellular functions and/or under stress conditions, prompting a reconsideration of its purely detrimental characterization. Moreover, this review highlights that distinguishing glycolysis as 'aerobic' and 'anaerobic' should not exist, as lactate is likely the final product of glycolysis, regardless of the presence of oxygen. Finally, this review explores the nuanced contributions of the Warburg effect beyond oncology, including its regulatory roles in various cellular environments and the potential effects on systemic physiological processes. By expanding our understanding of these mechanisms, we can uncover novel therapeutic strategies that target metabolic reprogramming, offering new avenues for treating cancer and other diseases characterized by metabolic dysregulation. This comprehensive reevaluation not only challenges traditional views but also enhances our understanding of cellular metabolism's adaptability and its implications in health and disease.

Keywords:  Warburg effect; cancer metabolism; cellular metabolism; glycolysis; metabolic reprogramming

DOI:  https://doi.org/10.31083/j.fbl2912402
Mol Metab. 2024 Dec 28. pii: S2212-8778(24)00220-5. [Epub ahead of print] 102089

Metabolic plasticity in pancreatic cancer: The mitochondrial connection.

Noemi Ghiglione, Damiano Abbo, Anastasia Bushunova, Andrea Costamagna, Paolo Ettore Porporato, Miriam Martini.

  Cellular metabolism plays a pivotal role in the development and progression of pancreatic ductal adenocarcinoma (PDAC), with dysregulated metabolic pathways contributing to tumorigenesis and therapeutic resistance. Distinct metabolic heterogeneity exists in pancreatic cancer, impacting patient prognosis, as variations in metabolic profiles influence tumor behavior and treatment responses. Here, we review the intricate interplay between mitochondrial dynamics, mitophagy, and cellular metabolism in PDAC. We highlight the significance of mitophagy dysregulation in PDAC pathogenesis, impacting treatment response and prognosis. Additionally, we examine the impact of mitochondrial dynamics alterations on PDAC progression, focusing on the role of fission and fusion processes in tumorigenesis. Ongoing trials have demonstrated the potential therapeutic value of targeting key regulators of mitochondrial dynamics and mitophagy. Despite challenges, targeting mitochondrial metabolism offers diverse strategies to enhance PDAC treatment efficacy, underscoring its potential in advancing cancer therapeutics.

Keywords:  Metabolism; Mitochondria; Mitophagy; Oxidative phosphorylation; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.molmet.2024.102089
Clin Transl Med. 2025 Jan;15(1): e70162

A new peptide inhibitor of C1QBP exhibits potent anti-tumour activity against triple negative breast cancer by impairing mitochondrial function and suppressing homologous recombination repair.

Xingxing Li, Yue Wu, Min Zhang, Fengliang Wang, Hong Yin, Yanrong Zhang, Shuli Zhao, Jiehua Ma, Mingming Lv, Cheng Lu.

  C1QBP exhibits heightened expression across a spectrum of tumours, thereby fostering their proliferation and metastasis, rendering it a pivotal therapeutic target. Nevertheless, to date, no pharmacological agents capable of directly targeting and inducing the degradation of C1QBP have been identified. In this study, we have unveiled a new peptide, PDBAG1, derived from the precursor protein GPD1, employing a peptidomics-based drug screening strategy. PDBAG1 has demonstrated substantial efficacy in suppressing triple-negative breast cancer (TNBC) both in vitro and in vivo. Its mechanism of action involves mitochondrial impairment and the inhibition of oxidative phosphorylation (OXPHOS), achieved through direct binding to C1QBP, thereby promoting its ubiquitin-dependent degradation. Concomitantly, due to metabolic adaptability, we have observed an up-regulation of glycolysis to compensate for OXPHOS inhibition. We observed an aberrant phenomenon wherein the hypoxia signalling pathway in tumour cells exhibited significant activation under normoxic conditions following PDBAG1 treatment. Through size-exclusion chromatography (SEC) and isothermal titration calorimetry (ITC) assays, we have validated that PDBAG1 is capable of binding C1QBP with a Kd value of 334 nM. Furthermore, PDBAG1 inhibits homologous recombination repair proteins and facilitates synergism with poly-ADP-ribose polymerase inhibitors in cancer therapy. This underscores that PDBAG1 ultimately induces insurmountable survival stress through multiple mechanisms while concurrently engendering therapeutic vulnerabilities specific to TNBC. KEY POINTS: The newly discovered peptide PDBAG1 is the first small molecule substance found to directly target and degrade C1QBP, demonstrating significant tumour inhibitory effects and therapeutic potential.

Keywords:  C1QBP; anti‐tumour peptide; homologous recombination repair; mitochondrial function; targeted protein degradation

DOI:  https://doi.org/10.1002/ctm2.70162
J Cancer. 2025 ;16(1): 227-240

Demethylzeylasteral inhibits oxidative phosphorylation complex biogenesis by targeting LRPPRC in lung cancer.

Lina Wang, Wei Zhou, Wenxi Wang, Yuxin Liang, Qiqi Xue, Zhen Zhang, Jinghe Yuan, Xiaohong Fang.

  Targeted inhibition of mitochondrial oxidative phosphorylation (OXPHOS) complex generation is an emerging and promising cancer treatment strategy, but limited targets and specific inhibitors have been reported. Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is an atypical RNA-binding protein that regulates the stability of all 13 mitochondrial DNA-encoded mRNA (mt-mRNA) and thus participates in the synthesis of the OXPHOS complex. LRPPRC is also a prospective therapeutic target for lung adenocarcinoma, serving as a promising target for OXPHOS inhibition. In this study, we identified Demethylzeylasteral (T-96), a small molecule extracted from the Chinese herb Tripterygium wilfordii Hook. f., as a novel inhibitor of LRPPRC. T-96 directly bound to the RNA-binding domain of LRPPRC, inhibiting its interaction with mt-mRNA. This led to instability in both mt-mRNA and LRPPRC protein. Treatment with T-96 significantly reduced the mRNA and protein levels of the OXPHOS complex. As a consequence of LRPPRC inhibition, T-96 treatment induced a defect in the synthesis of the OXPHOS complex, inhibiting mitochondrial aerobic respiration and ATP synthesis. Moreover, T-96 exhibited potent antitumor activity for lung adenocarcinoma in vitro and in vivo, and the antitumor effect of T-96 was dependent on LRPPRC expression. In conclusion, this study not only identified the first traditional Chinese medicine monomer inhibitor against OXPHOS complex biosynthesis as well as a novel target of Demethylzeylasteral, but also shed light on the unique antitumor mechanism of bioactive compounds derived from traditional Chinese medicine.

Keywords:  Demethylzeylasteral (T-96); LRPPRC; OXPHOS; Traditional Chinese Medicine (TCM); lung cancer

DOI:  https://doi.org/10.7150/jca.92797
Sci Rep. 2024 Dec 30. 14(1): 31589

The relationship between mitochondrial health, telomerase activity and longitudinal telomere attrition, considering the role of chronic stress.

Mauricio Guillen-Parra, Jue Lin, Aric A Prather, Owen M Wolkowitz, Martin Picard, Elissa S Epel.

  Telomere attrition is a hallmark of biological aging, contributing to cellular replicative senescence. However, few studies have examined the determinants of telomere attrition in vivo in humans. Mitochondrial Health Index (MHI), a composite marker integrating mitochondrial energy-transformation capacity and content, may be one important mediator of telomere attrition, as it could impact telomerase activity, a direct regulator of telomere maintenance. In this observational longitudinal study, we examined in peripheral blood mononuclear cells (PBMCs), whether MHI predicted changes in telomerase activity over a 9-month period, thus impacting telomere maintenance over this same period of time. We secondarily examined the role of chronic stress, by comparing these relationships in mothers of children with an autism spectrum disorder (caregivers) vs. mothers of a neurotypical child (controls). Here we show that both chronic stress exposure and lower MHI independently predicted decreases in telomerase activity over the subsequent 9 months. Finally, changes in telomere length were directly related with changes in telomerase activity, and indirectly with MHI and chronic stress, as revealed by a path analysis. These results highlight the potential role of chronic stress and MHI as drivers of telomere attrition in human PBMCs, through an impairment of both energy-transformation capacity and telomerase production.

Keywords:  Chronic stress; Mitochondrial health; Telomerase activity; Telomere attrition

DOI:  https://doi.org/10.1038/s41598-024-77279-9
Sci Rep. 2024 Dec 28. 14(1): 31401

Imaging phenotype reveals that disulfirams induce protein insolubility in the mitochondrial matrix.

Ken Ohno, Hisashi Murakami, Naohisa Ogo, Akira Asai.

  The cell painting assay is useful for understanding cellular phenotypic changes and drug effects. To identify other aspects of well-known chemicals, we screened 258 compounds with the cell painting assay and focused on a mitochondrial punctate phenotype seen with disulfiram. To elucidate the reason for this punctate phenotype, we looked for clues by examining staining steps and gene knockdown as well as examining protein solubility and comparing cell lines. From these results, we found that the punctate phenotype was caused by protein insolubility in the mitochondrial matrix. Interestingly, the punctate phenotype of disulfiram was sensitive to the relative expression of LonP1, a protease in the mitochondrial matrix that regulates proteostasis, suggesting that the punctate phenotype manifests when the protein quality control capacity in the mitochondrial matrix is exceeded. Moreover, we discovered that disulfiram and its derivatives, which have all been reported to increase acetaldehyde in the blood after the in vivo intake of alcohol, induced a punctate phenotype as well. The investigated punctate phenotype not only provides a novel clue for elucidating the common mechanism of action among disulfiram derivatives but is also a novel example of chemical perturbation of proteostasis in the mitochondrial matrix.

Keywords:  Cell painting assay; Disulfiram; LonP1; Oligomycin A; Protein insolubility; Proteostasis

DOI:  https://doi.org/10.1038/s41598-024-82939-x
Dev Cell. 2024 Dec 19. pii: S1534-5807(24)00732-9. [Epub ahead of print]

Aging-induced changes in lymphatic muscle cell transcriptomes are associated with reduced pumping of peripheral collecting lymphatic vessels in mice.

Pin-Ji Lei, Katarina J Ruscic, Kangsan Roh, Johanna J Rajotte, Meghan J O'Melia, Echoe M Bouta, Marla Marquez, Ethel R Pereira, Ashwin S Kumar, Mohammad S Razavi, Hengbo Zhou, Lutz Menzel, Liqing Huang, Heena Kumra, Mark Duquette, Peigen Huang, James W Baish, Lance L Munn, Natasza A Kurpios, Jessalyn M Ubellacker, Timothy P Padera.

  Lymphatic muscle cells (LMCs) within the wall of collecting lymphatic vessels exhibit tonic and autonomous phasic contractions, which drive active lymph transport to maintain tissue-fluid homeostasis and support immune surveillance. Damage to LMCs disrupts lymphatic function and is related to various diseases. Despite their importance, knowledge of the gene transcriptional signatures in LMCs and how they relate to lymphatic function in normal and disease contexts is largely missing. We have generated a comprehensive transcriptional single-cell atlas-including LMCs-of peripheral collecting lymphatic vessels from mice across the lifespan. We identified genes that distinguish LMCs from other types of muscle cells, characterized the phenotypical and transcriptomic changes in LMCs in aged vessels, and identified a proinflammatory microenvironment that suppresses the contractile apparatus in LMCs from advanced-aged mice. Our findings provide a valuable resource to accelerate future research for the identification of potential drug targets on LMCs to improve lymphatic vessel function.

Keywords:  aging; ion channel; lymphatic muscle cells; lymphatic pumping; single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.devcel.2024.12.010