Newly imported proteins in mitochondria are particularly sensitive to aggregation DOI Creative Commons
Carmela Vazquez‐Calvo, Verena Kohler, Johanna L. Höög

et al.

Acta Physiologica, Journal Year: 2023, Volume and Issue: 238(3)

Published: May 12, 2023

A functional proteome is essential for life and maintained by protein quality control (PQC) systems in the cytosol organelles. Protein aggregation an indicator of a decline PQC linked to aging disease. Mitochondrial critical maintain mitochondrial function thus cellular fitness. How mitochondria handle aggregated proteins not well understood. Here we tested how metabolic status impacts on formation clearance aggregates within yeast assessed which are particularly sensitive denaturation.

Language: Английский

Potential of Copper and Copper Compounds for Anticancer Applications DOI Creative Commons
Peng Ji, Peng Wang, Hao Chen

et al.

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(2), P. 234 - 234

Published: Feb. 3, 2023

Inducing cancer cell death has always been a research hotspot in life sciences. With the continuous deepening and diversification of related research, potential value metal elements inducing explored. Taking iron as an example, ferroptosis, mainly characterized by increasing load driving production large amounts lipid peroxides eventually leading to death, recently attracted great interest community. After iron, copper, trace element, received extensive attention especially tumor death. Copper its complexes can induce autophagy or apoptosis cells through variety different mechanisms action (activation stress pathways, arrest cycle, inhibition angiogenesis, cuproptosis, paraptosis), which are promising therapy have become new hotspots treatment research. This article reviews main applications novel copper compound-induced focusing on compounds their anticancer applications.

Language: Английский

Citations

89
Irisin regulates oxidative stress and mitochondrial dysfunction through the UCP2-AMPK pathway in prion diseases DOI Creative Commons

Pei Wen,

Zhixin Sun,

Dongming Yang

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 3, 2025

Abstract Prion diseases are a group of fatal neurodegenerative disorders characterized by the abnormal folding cellular prion proteins into pathogenic forms. The development these is intricately linked to oxidative stress and mitochondrial dysfunction. Irisin, an endogenous myokine, has demonstrated considerable neuroprotective potential due its antioxidative properties. However, protective effects irisin against have yet be clarified. Our findings indicate that treatment with exogenous can mitigate apoptosis induced PrP 106–126. Additionally, significantly reduces alleviates dysfunction triggered 106–126 . Furthermore, targets uncoupling protein 2 (UCP2) activates AMPK-Nrf2 pathway, substantially improving in N2a cells These results suggest represents novel promising therapeutic approach for treating diseases.

Language: Английский

Citations

2
Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies DOI Creative Commons
Jinze Shen,

Qurui Wang,

Yunan Mao

et al.

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 28, 2023

Tumor suppressor p53 can transcriptionally activate downstream genes in response to stress, and then regulate the cell cycle, DNA repair, metabolism, angiogenesis, apoptosis, other biological responses. has seven functional domains 12 splice isoforms, different subtypes play roles. The activation inactivation of are finely regulated associated with phosphorylation/acetylation modification ubiquitination modification, respectively. Abnormal is closely related occurrence development cancer. While targeted therapy signaling pathway still its early stages only a few drugs or treatments have entered clinical trials, new ongoing trials expected lead widespread use signaling-targeted cancer treatment future. TRIAP1 novel inhibitor apoptosis. homolog yeast mitochondrial intermembrane protein MDM35, which tumor-promoting role by blocking mitochondria-dependent apoptosis pathway. This work provides systematic overview recent basic research progress proposes that an important therapeutic target signaling.

Language: Английский

Citations

26
Tumor cell metabolic reprogramming and hypoxic immunosuppression: driving carcinogenesis to metastatic colonization DOI Creative Commons
Theodora Katopodi, Savvas Petanidis, Doxakis Anestakis

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 16, 2024

A significant factor in the antitumor immune response is increased metabolic reprogramming of immunological and malignant cells. Increasing data points to fact that cancer metabolism affects not just signaling, which essential for maintaining carcinogenesis survival, but also expression cells immune-related factors such as lactate, PGE2, arginine, IDO, regulate signaling mechanism. In reality, this energetic interaction between system tumor results competition ecosystem, limiting amount nutrients available causing microenvironmental acidosis, impairs ability operate. More intriguingly, different types use keep body self a state homeostasis. The process cell proliferation, differentiation, performance effector functions, crucial response, are currently being linked reprogramming. Here, we cover regulation by well potential strategies pathway targeting context anticancer immunotherapy. We discuss prospective immunotherapy-metabolic intervention combinations might be utilized maximize effectiveness current immunotherapy regimes.

Language: Английский

Citations

8
Mitochondria‐Modulating Liposomes Reverse Radio‐Resistance for Colorectal Cancer DOI Creative Commons

Junmei Li,

Yuhong Wang,

Wenhao Shen

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(18)

Published: March 23, 2024

Complete remission of colorectal cancer (CRC) is still unachievable in the majority patients by common fractionated radiotherapy, leaving risks tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference phosphorylation translation initiation factor eIF2α (p-eIF2α) activating transcription 4 (ATF4), whose increased expression initial X-ray irradiation led to resistance subsequent radiotherapy. The underlying mechanism studied radio-resistant CT26 cells, revealing that incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered key for elevated p-eIF2α ATF4, therefore radio-resistance. This finding guided discover metformin 2-DG are synergistic reversing radio inhibiting ATF4. Liposomes loaded with (M/D-Lipo) thus prepared enhancing radiotherapy CRC, which achieved satisfactory therapeutic efficacy both local metastatic tumors radio-resistance preventing T lymphocyte exhaustion.

Language: Английский

Citations

7
Translational response to mitochondrial stresses is orchestrated by tRNA modifications DOI Creative Commons
Sherif Rashad,

Shadi Al-Mesitef,

Abdulrahman Mousa

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 14, 2024

Abstract Mitochondrial stress and dysfunction play important roles in many pathologies. However, how cells respond to mitochondrial is not fully understood. Here, we examined the translational response electron transport chain (ETC) inhibition arsenite induced stresses. Our analysis revealed that during stress, tRNA modifications (namely f5C, hm5C, queuosine its derivatives, mcm5U) dynamically change fine tune codon decoding, usage, optimality. These changes optimality drive translation of pathways gene sets, such as ATF4 pathway selenoproteins, involved cellular stress. We further several these using targeted approaches. ALKBH1 knockout (KO) abrogated f5C hm5C levels led dysfunction, reduced proliferation, impacted mRNA rates. (tRNA-Q) a master regulator response. KO QTRT1 or QTRT2, enzymes responsible for tRNA-Q synthesis, dysregulation, metabolic alterations mitochondria-related pathways, without altering proliferation. In addition, our loss domino effect on various modifications. Some could be explained by profiling. also utilizing serum deprivation alteration with Queuine supplementation study can introduce confounding factors other summary, data show are regulators driving decoding.

Language: Английский

Citations

6
Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression DOI Creative Commons
Nils Grotehans, Lynn McGarry, Hendrik Nolte

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(18)

Published: July 13, 2023

Replication of the mitochondrial genome and expression genes it encodes both depend on a sufficient supply nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises genome, but also affects its transcription. Here, we report that nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides are necessary for transcription genes. Loss NME6 function leads depletion transcripts, as well destabilisation electron transport chain impaired oxidative phosphorylation. These deficiencies rescued by an exogenous ribonucleosides. Moreover, is required maintenance DNA when access cytosolic deoxyribonucleotides limited. Our results therefore reveal important role ribonucleotide salvage in gene expression.

Language: Английский

Citations

16
The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage DOI Creative Commons
Pablo Rivera-Mejías, Álvaro Jesús Narbona‐Pérez,

Lidwina Hasberg

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(4), P. 112332 - 112332

Published: March 31, 2023

The metabolic plasticity of mitochondria ensures cell development, differentiation, and survival. peptidase OMA1 regulates mitochondrial morphology via OPA1 stress signaling DELE1 orchestrates tumorigenesis survival in a cell- tissue-specific manner. Here, we use unbiased systems-based approaches to show that OMA1-dependent depends on cues. A metabolism-focused CRISPR screen combined with an integrated analysis human gene expression data found protects against DNA damage. Nucleotide deficiencies induced by chemotherapeutic agents promote p53-dependent apoptosis cells lacking OMA1. protective effect does not depend activation or OMA1-mediated processing. OMA1-deficient reduced glycolysis accumulate oxidative phosphorylation (OXPHOS) proteins upon OXPHOS inhibition restores confers resistance Thus, dictates the balance between death through control glucose metabolism, shedding light its role cancerogenesis.

Language: Английский

Citations

15
Discovery of a Novel Series of Homo sapiens Caseinolytic Protease P Agonists for Colorectal Adenocarcinoma Treatment via ATF3-Dependent Integrated Stress Response DOI
Jiangnan Zhang, Zhiqiang Qiu, Song Liu

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(4), P. 2812 - 2836

Published: Feb. 8, 2024

Homo sapiens caseinolytic protease P (HsClpP) activation is a promising strategy for colon cancer treatment. In this study, CCG1423 was identified as selective activator of HsClpP. After optimization, NCA029 emerged the most potent compound, with an EC50 0.2 μM against Molecular dynamics revealed that affinity YYW aromatic network crucial its selectivity toward Furthermore, displayed favorable pharmacokinetics and safety profiles significantly inhibited tumor growth in HCT116 xenografts, resulting 83.6% inhibition. Mechanistically, targeted HsClpP, inducing mitochondrial dysfunction activating ATF3-dependent integrated stress response, ultimately causing cell death colorectal adenocarcinoma. These findings highlight effective HsClpP potential therapy.

Language: Английский

Citations

5
Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy DOI Creative Commons
Sofia Ahola, Lilli A. Pazurek,

Fiona Carola Mayer

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(31)

Published: Aug. 2, 2024

Mitochondrial fusion and fission accompany adaptive responses to stress altered metabolic demands. Inner membrane cristae morphogenesis depends on optic atrophy 1 (Opa1), which is expressed in different isoforms cleaved from a membrane-bound, long soluble, short form. Here, we have analyzed the physiological role of Opa1 processing by generating mouse lines expressing only one cleavable isoform or non-cleavable variant thereof. Our results show that expression single preserves embryonic development health adult mice. dispensable under thermal but prolongs life span protects against mitochondrial cardiomyopathy OXPHOS-deficient Cox10 −/− Mechanistically, loss disturbs balance between biogenesis mitophagy, suppressing cardiac hypertrophic growth hearts. highlight critical regulatory processing, dynamics, metabolism for hypertrophy.

Language: Английский

Citations

5