Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction.
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ABSTRACT:
SUBMITTER: Peruzzo R
PROVIDER: S-EPMC8032734 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at the lower end of the size distribution. Here, we show that the mitochondrial proteome, particularly the respiratory chain, is enriched for small proteins. Using a prediction and validation pipeline for SEPs, we report the discovery of 16 endogenous nuclear encoded, mitochondrial-localized SEPs (mito-SEPs). Through functional prediction, proteomics, metabolomics and metabolic flux modeling, we demonstrate that BRAWNIN, a 71 a.a. peptide encoded by C12orf73, is essential for respiratory chain complex III (CIII) assembly. In human cells, BRAWNIN is induced by the energy-sensing AMPK pathway, and its depletion impairs mitochondrial ATP production. In zebrafish, Brawnin deletion causes complete CIII loss, resulting in severe growth retardation, lactic acidosis and early death. Our findings demonstrate that BRAWNIN is essential for vertebrate oxidative phosphorylation. We propose that mito-SEPs are an untapped resource for essential regulators of oxidative metabolism.
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Project description:Plant oxylipins are signaling molecules produced from fatty acids by oxidative pathways, mainly initiated by 9- and 13-lipoxygenases (9-LOX and 13-LOX), alpha-dioxygenases or non-enzymatic oxidation. Oxylipins from the 9-LOX pathway induce oxidative stress and control root development and plant defense. These activities have been associated with mitochondrial processes, but precise cellular targets and pathways remain unknown. In order to study oxylipin signaling, we previously generated a collection of Arabidopsis thaliana mutants that were insensitive to the 9-LOX products 9(S)-hydroxy-10,12, 15-octadecatrienoic acid (9-HOT) and its ketone derivative 9-KOT (noxy mutants). Here, we describe noxy1, noxy3, noxy5, noxy23, and noxy54 mutants, all affected in nucleus-encoded mitochondrial proteins, and use them to study the role of mitochondria in oxylipin signaling. Functional and phenotypic analyses showed that noxy plants displayed mitochondrial aggregation, reduced respiration rates and resistance to the complex III inhibitor Antimycin A (AA), thus indicating a close similarity of the oxylipin signaling and mitochondrial stress. Application of 9-HOT and 9-KOT protected plants against subsequent mitochondrial stress, whereas they boosted root growth reduction when applied in combination with complex III inhibitors but did not with inhibitors of other respiratory complexes. A similar effect was caused by linear-chain oxylipins from 13-LOX or non-enzymatic pathways having α,β-unsaturated hydroxyl or keto groups in their structure. Studies to investigate 9-HOT and 9-KOT activity indicated that they do not reduce respiration rates, but their action is primarily associated with enhanced ROS responses. This was supported by the results showing that 9-HOT or 9-KOT combined with AA amplified the expression of oxylipin- and ROS-responding genes but not of the AA marker AOX1a, thus implying the activation of a specific mitochondria retrograde signaling pathway. Our results implicate mitochondrial complex III as a hub in the signaling activity of multiple oxylipin pathways and point at downstream ROS responses as components of oxylipin function.
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Project description:Metagenomics of the Respiratory disease complex in Poultry
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Project description:ObjectivesTo determine whether placental cell therapy PLacental eXpanded (PLX)-PAD (Pluristem Therapeutics, Haifa, Israel) may be beneficial to treating critically ill patients suffering from acute respiratory distress syndrome due to coronavirus disease 2019.DesignRetrospective case report of critically ill coronavirus disease 2019 patients treated with PLacental eXpanded (PLX)-PAD from March 26, 2020, to April 4, 2020, with follow-up through May 2, 2020.SettingFour hospitals in Israel (Rambam Health Care Campus, Bnai Zion Medical Center, and Samson Assuta Ashdod University Hospital), and Holy Name Medical Center in New Jersey.PatientsEight critically ill patients on invasive mechanical ventilation, suffering from acute respiratory distress syndrome due to coronavirus disease 2019.InterventionsIntramuscular injection of PLacental eXpanded (PLX)-PAD (300 × 106 cells) given as one to two treatments.Measurements and main resultsMortality, time to discharge, and changes in blood and respiratory variables were monitored during hospitalization to day 17 posttreatment. Of the eight patients treated (median age 55 yr, seven males and one female), five were discharged, two remained hospitalized, and one died. By day 3 postinjection, mean C-reactive protein fell 45% (240.3-131.3 mg/L; p = 0.0019) and fell to 77% by day 5 (56.0 mg/L; p < 0.0001). Pao2/Fio2 improved in 5:8 patients after 24-hour posttreatment, with similar effects 48-hour posttreatment. A decrease in positive end-expiratory pressure and increase in pH were statistically significant between days 0 and 14 (p = 0.0032 and p = 0.00072, respectively). A decrease in hemoglobin was statistically significant for days 0-5 and 0-14 (p = 0.015 and p = 0.0028, respectively), whereas for creatinine, it was statistically significant between days 0 and 14 (p = 0.032).ConclusionsImprovement in several variables such as C-reactive protein, positive end-expiratory pressure, and Pao2/Fio2 was observed following PLacental eXpanded (PLX)-PAD treatment, suggesting possible therapeutic effect. However, interpretation of the data is limited due to the small sample size, use of concomitant investigational therapies, and the uncontrolled study design. The efficacy of PLacental eXpanded (PLX)-PAD in coronavirus disease 2019 should be further evaluated in a controlled clinical trial.
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