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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186751 | GEO | 2022/01/01

REPOSITORIES: GEO

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Project description:This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PTEN-induced putative kinase 1 (PINK1)-Parkin mediated mitophagy, NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation, and apoptosis. We found that recombinant DEK protein (rmDEK) promoted eosinophils recruitment, mitochondrial fragmentation, and outer membrane 20 (TOM20) and LC3 co-localization representing mitophagosomes in bronchoalveolar lavage fluid (BALF) in house dust mite (HDM) induced-asthma. rmDEK also reduced co-localization of mitochondrial fusion protein mitofusin1 (MFN1) and mitochondria, and the protein level of manganese superoxide dismutase (MnSOD), enhanced microtubule-associated protein1 light chain 3 (LC3) and voltage-dependent anion channels (VDAC) co-localization which also represent the mitophagosomes in airway epithelial cells, furthermore, increased dynamin-related protein 1 (DRP1) expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. In the DEK knockout mice, HDM induced asthmatic airway inflammation, MnSOD, PINK1-Parkin protein level, Parkin mediated mitophagy characterized by LC3 and Parkin co-localization in the airways, ROS generation, NLRP3 inflammation and apoptosis were fully reversed. Similar effects of rmDEK were also observed in the BEAS-2B cells, which were rescued by the autophagy inhibitor 3-MA. Moreover, DEK silencing diminished the Parkin, LC3, DRP1 translocation to mitochondria; as well as mitochondrial ROS; TOM20 and mitochondrial DNA mediated mitochondrial oxidative damage. ChIP-sequence analysis showed that DEK was enriched on the AAA domain-containing protein 3A (ATAD3A) promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models. Furthermore, ATAD3A interacted with DRP1, and knockdown of ATAD3A could down-regulate DRP1 and mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.

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

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