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Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon.

ABSTRACT: The mitochondrial electron transport chain is a major source of reactive oxygen species (ROS) and is also a target of ROS, with an implied role in the stabilization of hypoxia-inducible factor (HIF) and induction of the AMPK pathway. Here we used varying doses of two agents, Mito-Paraquat and Mito-Metformin, that have been conjugated to cationic triphenylphosphonium (TPP⁺) moiety to selectively target them to the mitochondrial matrix compartment, thereby resulting in the site-specific generation of ROS within mitochondria. These agents primarily induce superoxide (O₂^•-) production by acting on complex I. In Raw264.7 macrophages, C2C12 skeletal myocytes, and HCT116 adenocarcinoma cells, we show that mitochondria-targeted oxidants can induce ROS (O₂^•- and H₂O₂). In all three cell lines tested, the mitochondria-targeted agents disrupted membrane potential and activated calcineurin and the Cn-dependent retrograde signaling pathway. Hypoxic culture conditions also induced Cn activation and HIF1α activation in a temporally regulated manner, with the former appearing at shorter exposure times. Together, our results indicate that mitochondrial oxidant-induced retrograde signaling is driven by disruption of membrane potential and activation of Ca²⁺/Cn pathway and is independent of ROS-induced HIF1α or AMPK pathways.

SUBMITTER: Chowdhury AR

PROVIDER: S-EPMC7327929 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Deficient Pink1 Retrograde Mitochondrial-Nrf2 Signaling Induces EMT That Is Mitigated By A Mitochondria-tropic ROS Reducing Dendrimer

Project description:Age-related macular degeneration (AMD), the leading cause of blindness among the elderly, is without effective treatment for early, dry disease. Retinal pigment epithelial (RPE) cell degeneration is a cardinal feature of dry AMD. Given the reliance of photoreceptors on the RPE for maintaining health and vision, rejuvenating dysfunctional RPE is a logical treatment strategy. Here, the interplay between two cytoprotective pathways, Pink1 mediated mitophagy and the Nrf2 stress-response, was studied in human AMD tissue samples, RPE cells, and relevant mouse models. Pink1 immunolabeling was decreased in the RPE of early AMD eyes. The RPE from Pink1-/- mice and Pink1 deficient cultured human RPE cells displayed impaired mitophagy, decreased aerobic respiration, and increased mitochondrial reactive oxygen species (ROS) generation, and coincidently, developed morphological, molecular, and functional features of epithelial-mesenchymal transition (EMT). This change was triggered by novel retrograde mitochondrial to nuclear signaling that was initiated by mitochondrial ROS, which activated Nrf2 to induce TXNRD1, PI3K/AKT, and canonical EMT transcription factors Zeb1 and Snail. Nrf2 signaling was pivotal since its deficiency prevented EMT and increased cell death. A dendrimer containing N-acetyl cysteine that is tropic for the RPE and contains the mitochondrial targeting ligand Triphenyl phosphinium abrogates EMT in human RPE cells in vitro and in Pink1-/- mice. This study describes a novel interdependency of mitophagy and the Nrf2 antioxidant response in determining cell fate and introduces an RPE and mitochondrial specific ROS reducing dendrimer that can rescue RPE cells in EMT, a change recognized in early AMD.

2022-01-01 | GSE186751 | GEO

Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells.

Project description:Metformin (Met) is an approved antidiabetic drug currently being explored for repurposing in cancer treatment based on recent evidence of its apparent chemopreventive properties. Met is weakly cationic and targets the mitochondria to induce cytotoxic effects in tumor cells, albeit not very effectively. We hypothesized that increasing its mitochondria-targeting potential by attaching a positively charged lipophilic substituent would enhance the antitumor activity of Met. In pursuit of this question, we synthesized a set of mitochondria-targeted Met analogues (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP(+)). In particular, the analogue Mito-Met10, synthesized by attaching TPP(+) to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells, Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in nontransformed control cells. Moreover, Mito-Met10 potently triggered G1 cell-cycle phase arrest in PDAC cells, enhanced their radiosensitivity, and more potently abrogated PDAC growth in preclinical mouse models, compared with Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including aggressive cancers like PDAC in great need of more effective therapeutic options. Cancer Res; 76(13); 3904-15. ©2016 AACR.

| S-EPMC4930686 | biostudies-literature

Non-esterified Fatty Acid Induce Dairy Cow Hepatocytes Apoptosis via the Mitochondria-Mediated ROS-JNK/ERK Signaling Pathway.

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DnmA and FisA Mediate Mitochondria and Peroxisome Fission, and Regulate Mitochondrial Function, ROS Production and Development in Aspergillus nidulans.

Project description:The dynamin-like protein Drp1 and its receptor Fis-1 are required for mitochondria and peroxisome fission in animal and yeast cells. Here, we show that in the fungus Aspergillus nidulans the lack of Drp1 and Fis-1 homologs DnmA and FisA has strong developmental defects, leading to a notable decrease in hyphal growth and asexual and sexual sporulation, with some of these defects being aggravated or partially remediated by different carbon sources. Although both DnmA and FisA, are essential for mitochondrial fission, participate in peroxisomal division and are fully required for H2O2-induced mitochondrial division, they also appear to play differential functions. Despite their lack of mitochondrial division, ?dnmA and ?fisA mutants segregate mitochondria to conidiogenic cells and produce viable conidia that inherit a single mitochondrion. During sexual differentiation, ?dnmA and ?fisA mutants develop fruiting bodies (cleistothecia) that differentiate excessive ascogenous tissue and a reduced number of viable ascospores. ?dnmA and ?fisA mutants show decreased respiration and notably high levels of mitochondrial reactive oxygen species (ROS), which likely correspond to superoxide. Regardless of this, ?dnmA mutants can respond to an external H2O2 challenge by re-localizing the MAP kinase-activated protein kinase (MAPKAP) SrkA from the cytoplasm to the nuclei. Our results show that ROS levels regulate mitochondrial dynamics while a lack of mitochondrial fission results in lower respiration, increased mitochondrial ROS and developmental defects, indicating that ROS, mitochondrial division and development are critically interrelated processes.

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Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy.

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| S-EPMC8617807 | biostudies-literature

Prochelator BHAPI protects cells against paraquat-induced damage by ROS-triggered iron chelation.

Project description:A prochelator named BHAPI (N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide) based on the structure of experimental metal chelator HAPI (N'-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide) has been synthesized. The prochelator, which shows limited affinity for metal ions, is converted efficiently upon reaction with hydrogen peroxide into its chelator form, which binds di- and trivalent metal ions, including Zn(2+), Cu(2+) and Fe(3+). This work shows that the prochelator has a protective effect on cells under oxidative stress induced by either hydrogen peroxide or the cytotoxic herbicide paraquat. The effect of BHAPI and HAPI on cellular iron status was assessed by monitoring the mRNA level of the transferrin receptor. Whereas the chelator HAPI induces iron deficiency in cultured retinal pigment epithelial cells, the prochelator does not, providing evidence that the differential metal-binding capacity of these compounds observed in vitro is replicated in the cellular context.

| S-EPMC3427476 | biostudies-literature

Mitochondria-Targeted Drugs.

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| S-EPMC6875871 | biostudies-literature

Multivesicular bodies mediate long-range retrograde NGF-TrkA signaling.

Project description:The development of neurons in the peripheral nervous system is dependent on target-derived, long-range retrograde neurotrophic factor signals. The prevailing view is that target-derived nerve growth factor (NGF), the prototypical neurotrophin, and its receptor TrkA are carried retrogradely by early endosomes, which serve as TrkA signaling platforms in cell bodies. Here, we report that the majority of retrograde TrkA signaling endosomes in mouse sympathetic neurons are ultrastructurally and molecularly defined multivesicular bodies (MVBs). In contrast to MVBs that carry non-TrkA cargoes from distal axons to cell bodies, retrogradely transported TrkA+ MVBs that arrive in cell bodies evade lysosomal fusion and instead evolve into TrkA+ single-membrane vesicles that are signaling competent. Moreover, TrkA kinase activity associated with retrogradely transported TrkA+ MVBs determines TrkA+ endosome evolution and fate. Thus, MVBs deliver long-range retrograde NGF signals and serve as signaling and sorting platforms in the cell soma, and MVB cargoes dictate their vesicular fate.

| S-EPMC5811214 | biostudies-literature

Communication between mitochondria and nucleus: defining a retrograde response in fission yeast

Project description:Retrograde response was widely studied in budding yeast but the main transcription factors that transmit it (RTG1,2 and 3) are not conserved in other organisms, thus it is interesting to study how communication between mitochondria and nucleus evolved in distantly related fission yeast, and which are the common aspects of this conserved pathway between yeast and higher organisms.To analyse any retrograde response in fission yeast, we inhibited the electron transport chain activity by antimycin A and studied cellular gene expression changes by microarrays. Cells treated with antimycin A in fermentative medium (YE with 3% glucose), showed the same growth rate as untreated cells, but they reached a lower biomass in stationary phase. Antimycin A treated cells consumed glucose at a faster rate and produced more ethanol, indicating that the energy metabolism was shifted even more towards fermentation. We analyzed the transcriptomes of antimycin A-treated cells to untreated control cells during early exponential growth phase (OD 0.5).

2016-11-01 | E-MTAB-4520 | biostudies-arrayexpress

Neurexin and neuroligin mediate retrograde synaptic inhibition in C. elegans.

Project description:The synaptic adhesion molecules neurexin and neuroligin alter the development and function of synapses and are linked to autism in humans. Here, we found that Caenorhabditis elegans neurexin (NRX-1) and neuroligin (NLG-1) mediated a retrograde synaptic signal that inhibited neurotransmitter release at neuromuscular junctions. Retrograde signaling was induced in mutants lacking a muscle microRNA (miR-1) and was blocked in mutants lacking NLG-1 or NRX-1. Release was rapid and abbreviated when the retrograde signal was on, whereas release was slow and prolonged when retrograde signaling was blocked. The retrograde signal adjusted release kinetics by inhibiting exocytosis of synaptic vesicles (SVs) that are distal to the site of calcium entry. Inhibition of release was mediated by increased presynaptic levels of tomosyn, an inhibitor of SV fusion.

| S-EPMC3791080 | biostudies-literature

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