Browse
Submit Data
Databases
API
Help

Dataset Information

4 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A peptide-derived strategy for specifically targeting the mitochondria and ER of cancer cells: a new approach in fighting cancer.

ABSTRACT: An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance. Here, we present a new approach in cancer therapy that specifically targets the mitochondria and ER of cancer cells. We developed a peptide derived from the flexible and transmembrane domains of the human protein NAF-1/CISD2. This peptide (NAF-1^44-67) specifically permeates through the plasma membranes of human epithelial breast cancer cells, abolishes their mitochondria and ER, and triggers cell death with characteristics of apoptosis, ferroptosis and necroptosis. In vivo analysis revealed that the peptide significantly decreases tumor growth in mice carrying xenograft human tumors. Computational simulations of cancer vs. normal cell membranes reveal that the specificity of the peptide to cancer cells is due to its selective recognition of their membrane composition. NAF-1^44-67 represents a promising anti-cancer lead compound that acts via a unique mechanism.

SUBMITTER: Sohn YS

PROVIDER: S-EPMC9200128 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A peptide-derived strategy for specifically targeting the mitochondrial-ER network of cancer cells: a new paradigm in fighting cancer

Project description:An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance. Here, we present a novel paradigm in cancer therapy that specifically targets the mitochondria and ER of cancer cells. We developed a peptide derived from the flexible and transmembrane domains of the human protein NAF-1/CISD2. This peptide (NAF-1) specifically permeated through the plasma membranes of human epithelial breast cancer cells, abolished their mitochondrial-ER network, and triggered cell death with characteristics of apoptosis, ferroptosis and necroptosis. In vivo analysis revealed that the peptide significantly decreased tumor growth in mice carrying xenograft human tumors. Computational simulations of cancer vs. normal cells membranes revealed that the specificity of the peptide to cancer cells is due to its selective recognition of their membrane composition. NAF-1 represents therefore a promising anti-cancer lead compound that acts via a unique mechanism.

2022-08-12 | PXD030509 | Pride

Dual peptide conjugation strategy for improved cellular uptake and mitochondria targeting.

Project description:Mitochondria are critical regulators of cellular function and survival. Delivery of therapeutic and diagnostic agents into mitochondria is a challenging task in modern pharmacology because the molecule to be delivered needs to first overcome the cell membrane barrier and then be able to actively target the intracellular organelle. Current strategy of conjugating either a cell penetrating peptide (CPP) or a subcellular targeting sequence to the molecule of interest only has limited success. We report here a dual peptide conjugation strategy to achieve effective delivery of a non-membrane-penetrating dye 5-carboxyfluorescein (5-FAM) into mitochondria through the incorporation of both a mitochondrial targeting sequence (MTS) and a CPP into one conjugated molecule. Notably, circular dichroism studies reveal that the combined use of ?-helix and PPII-like secondary structures has an unexpected, synergistic contribution to the internalization of the conjugate. Our results suggest that although the use of positively charged MTS peptide allows for improved targeting of mitochondria, with MTS alone it showed poor cellular uptake. With further covalent linkage of the MTS-5-FAM conjugate to a CPP sequence (R8), the dually conjugated molecule was found to show both improved cellular uptake and effective mitochondria targeting. We believe these results offer important insight into the rational design of peptide conjugates for intracellular delivery.

| S-EPMC4306504 | biostudies-literature

Plant-derived mitochondria-targeting cysteine-rich peptide modulates cellular bioenergetics.

Project description:Mitochondria are attractive therapeutic targets for developing agents to delay age-related frailty and diseases. However, few promising leads have been identified from natural products. Previously, we identified roseltide rT1, a hyperstable 27-residue cysteine-rich peptide from Hibiscus sabdariffa, as a knottin-type neutrophil elastase inhibitor. Here, we show that roseltide rT1 is also a cell-penetrating, mitochondria-targeting peptide that increases ATP production. Results from flow cytometry, live-cell imaging, pulldown assays, and genetically-modified cell lines supported that roseltide rT1 enters cells via glycosaminoglycan-dependent endocytosis, and enters the mitochondria through TOM20, a mitochondrial protein import receptor. We further showed that roseltide rT1 increases cellular ATP production via mitochondrial membrane hyperpolarization. Using biotinylated roseltide rT1 for target identification and proteomic analysis, we showed that human mitochondrial membrane ATP synthase subunit O is an intramitochondrial target. Collectively, these data support our discovery that roseltide rT1 is a first-in-class mitochondria-targeting, cysteine-rich peptide with potentials to be developed into tools to further our understanding of mitochrondria-related diseases.

| S-EPMC6422099 | biostudies-literature

Mitochondria Targeting as an Effective Strategy for Cancer Therapy.

Project description:Mitochondria are well known for their role in ATP production and biosynthesis of macromolecules. Importantly, increasing experimental evidence points to the roles of mitochondrial bioenergetics, dynamics, and signaling in tumorigenesis. Recent studies have shown that many types of cancer cells, including metastatic tumor cells, therapy-resistant tumor cells, and cancer stem cells, are reliant on mitochondrial respiration, and upregulate oxidative phosphorylation (OXPHOS) activity to fuel tumorigenesis. Mitochondrial metabolism is crucial for tumor proliferation, tumor survival, and metastasis. Mitochondrial OXPHOS dependency of cancer has been shown to underlie the development of resistance to chemotherapy and radiotherapy. Furthermore, recent studies have demonstrated that elevated heme synthesis and uptake leads to intensified mitochondrial respiration and ATP generation, thereby promoting tumorigenic functions in non-small cell lung cancer (NSCLC) cells. Also, lowering heme uptake/synthesis inhibits mitochondrial OXPHOS and effectively reduces oxygen consumption, thereby inhibiting cancer cell proliferation, migration, and tumor growth in NSCLC. Besides metabolic changes, mitochondrial dynamics such as fission and fusion are also altered in cancer cells. These alterations render mitochondria a vulnerable target for cancer therapy. This review summarizes recent advances in the understanding of mitochondrial alterations in cancer cells that contribute to tumorigenesis and the development of drug resistance. It highlights novel approaches involving mitochondria targeting in cancer therapy.

| S-EPMC7247703 | biostudies-literature

Targeting Microbiome: An Alternative Strategy for Fighting SARS-CoV-2 Infection.

Project description:Respiratory and gastrointestinal symptoms are the predominant clinical manifestations of the coronavirus disease 2019 (COVID-19). Infecting intestinal epithelial cells, the severe acute respiratory syndrome coronavirus-2 may impact on host's microbiota and gut inflammation. It is well established that an imbalanced intestinal microbiome can affect pulmonary function, modulating the host immune response ("gut-lung axis"). While effective vaccines and targeted drugs are being tested, alternative pathophysiology-based options to prevent and treat COVID-19 infection must be considered on top of the limited evidence-based therapy currently available. Addressing intestinal dysbiosis with a probiotic supplement may, therefore, be a sensible option to be evaluated, in addition to current best available medical treatments. Herein, we summed up pathophysiologic assumptions and current evidence regarding bacteriotherapy administration in preventing and treating COVID-19 pneumonia.

| S-EPMC8089442 | biostudies-literature

ER-mitochondria contacts promote mitochondrial-derived compartment biogenesis.

Project description:Mitochondria are dynamic organelles with essential roles in signaling and metabolism. We recently identified a cellular structure called the mitochondrial-derived compartment (MDC) that is generated from mitochondria in response to amino acid overabundance stress. How cells form MDCs is unclear. Here, we show that MDCs are dynamic structures that form and stably persist at sites of contact between the ER and mitochondria. MDC biogenesis requires the ER-mitochondria encounter structure (ERMES) and the conserved GTPase Gem1, factors previously implicated in lipid exchange and membrane tethering at ER-mitochondria contacts. Interestingly, common genetic suppressors of abnormalities displayed by ERMES mutants exhibit distinct abilities to rescue MDC formation in ERMES-depleted strains and are incapable of rescuing MDC formation in cells lacking Gem1. Thus, the function of ERMES and Gem1 in MDC biogenesis may extend beyond their conventional role in maintaining mitochondrial phospholipid homeostasis. Overall, this study identifies an important function for ER-mitochondria contacts in the biogenesis of MDCs.

| S-EPMC7588143 | biostudies-literature

The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria

Project description:Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER mitochondria encounter structure (ERMES) and Tom70, together with Djp1 and Lam6, are part of two parallel and partially redundant ER-to-mitochondria delivery routes. When ER-to-mitochondria transfer is prevented by loss of these two contact sites, many precursors of mitochondrial inner membrane proteins are left stranded on the ER membrane, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.

| S-SCDT-10_1038-S44319-024-00113-W | biostudies-other

Targeting Hydroxybenzoic Acids to Mitochondria as a Strategy to Delay Skin Ageing: An In Vitro Approach.

Project description:Targeting antioxidants to mitochondria is considered a promising strategy to prevent cellular senescence and skin ageing. In this study, we investigate whether four hydroxybenzoic acid-based mitochondria-targeted antioxidants (MitoBENs, MB1-4) could be used as potential active ingredients to prevent senescence in skin cells. Firstly, we evaluated the chemical stability, cytotoxicity, genotoxicity and mitochondrial toxicity of all compounds. We followed this by testing the antioxidant protective capacity of the two less toxic compounds on human skin fibroblasts. We then assessed the effects of the best hit on senescence, inflammation and mitochondrial remodeling on a 3D skin cell model, while also testing its mutagenic potential. Cytotoxicity and mitochondrial toxicity rankings were produced: MB3 < MB4 ≃ MB1 < MB2 and MB3 < MB1 < MB4 < MB2, respectively. These results suggest that pyrogallol-based compounds (MB2 and MB4) have lower cytotoxicity. The pyrogallol derivative, MB2, containing a 6-carbon spacer, showed a more potent antioxidant protective activity against hydrogen peroxide cytotoxicity. In a 3D skin cell model, MB2 also decreased transcripts related to senescence. In sum, MB2’s biological safety profile, good chemical stability and lack of mutagenicity, combined with its anti-senescence effect, converts MB2 into a good candidate for further development as an active ingredient for skin anti-ageing products.

| S-EPMC9571003 | biostudies-literature

Peptide nucleic acids targeting mitochondria enhances sensitivity of lung cancer cells to chemotherapy.

Project description:Acquired resistance to chemotherapy is a major limitation for the successful treatment of lung cancer. Previously, we and others showed that formation of tumor spheres is associated with chemotherapy resistance in lung cancer cells, but the underlying mechanisms remained largely unknown. In the current study, we show that mitochondrial activity is significantly higher in A549 tumor spheres versus monolayer cells, establishing mitochondria as a putative target for antitumor therapy. To this end, we designed a peptide nucleic acids (PNAs) coupled with triphenylphosphonium (TPP) to target the displacement loop (D-loop) regulatory region of mitochondrial DNA (PNA-mito). Treatment with PNA-mito significantly disrupted mitochondrial gene expression, inhibited membrane potential and mitochondria fusion, resulting in proliferation inhibition and cell death. Consistently, in mouse xenograft models, PNA-mito could efficiently inhibit mitochondrial gene expression and block tumor growth. Treatment with a low dose of PNA-mito could significantly enhance the chemotoxicity of cisplatin (CDDP) in drug-resistant A549 tumor spheres. These results establish mitochondria-targeting PNAs as a novel strategy to enhance the accumulative therapeutic outcome of lung cancer.

| S-EPMC6176231 | biostudies-literature

Targeting mitochondria as therapeutic strategy for metabolic disorders.

Project description:Mitochondria are critical regulator of cell metabolism; thus, mitochondrial dysfunction is associated with many metabolic disorders. Defects in oxidative phosphorylation, ROS production, or mtDNA mutations are the main causes of mitochondrial dysfunction in many pathological conditions such as IR/diabetes, metabolic syndrome, cardiovascular diseases, and cancer. Thus, targeting mitochondria has been proposed as therapeutic approach for these conditions, leading to the development of small molecules to be tested in the clinical scenario. Here we discuss therapeutic interventions to treat mitochondrial dysfunction associated with two major metabolic disorders, metabolic syndrome, and cancer. Finally, novel mechanisms of regulation of mitochondrial function are discussed, which open new scenarios for mitochondria targeting.

| S-EPMC3976884 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data