Polycystin‐1 regulates cardiomyocyte mitophagy

Ramírez‐Sagredo, Andrea; Quiroga, Clara; Garrido-Moreno, Valeria; López-Crisosto, Camila; Leiva-Navarrete, Sebastian; Norambuena-Soto, Ignacio; Ortiz‐Quintero, Jafet; Díaz-Vesga, Magda C; Perez, William M.; Hendrickson, Troy; Parra, Valentina; Pedrozo, Zully; Altamirano, Francisco; Chiong, Mario; Lavandero, Sergio

doi:10.1096/fj.202002598r

Cited by 12 publications

(13 citation statements)

References 54 publications

(153 reference statements)

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“…The ImageJ macro tool MiNA was used to analyze mitochondrial network morphology, 15 and cells with intact fibers were selected for the analysis. As for the analysis mitochondrial network in TEM images of mice, we selected 5 images per mouse for assessment ( n = 3), with approximately 25 mitochondria per image 16 …”

Section: Methodsmentioning

confidence: 99%

“…The images of mitochondria in the cells were photographed from five different fields of spotting, mitochondrial fragmentation was measured, and the data from 5 independent experiments were calculated using Image J software. Based on mitochondrial morphology, the cells from different groups were classified into 3 categories: hyperfused (at least one mitochondrion >5 μm in length), intermediate (at least one mitochondrion between 2 and 5 μm in length), and rounded (none mitochondrion longer than 2 μm) 16 . The cells were scored as fragmented when 90% of the tubular mitochondria was disintegrated 14,17 .…”

Section: Methodsmentioning

confidence: 99%

“…As for the analysis mitochondrial network in TEM images of mice, we selected 5 images per mouse for assessment (n = 3), with approximately 25 mitochondria per image. 16…”

Section: Transmission Electron Microscopy (Tem)mentioning

confidence: 99%

“…Based on mitochondrial morphology, the cells from different groups were classified into 3 categories: hyperfused (at least one mitochondrion >5 μm in length), intermediate (at least one mitochondrion between 2 and 5 μm in length), and rounded (none mitochondrion longer than 2 μm). 16 The cells were scored as fragmented when 90% of the tubular mitochondria was disintegrated. 14,17 The percentages of cells in each category were determined from 5 independent experiments, with a total of 125 cells/ group being analyzed.…”

Section: Mitochondrial Trackingmentioning

confidence: 99%

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Activation of FMS ‐like tyrosine kinase 3 protects against isoprenaline‐induced cardiac hypertrophy by improving autophagy and mitochondrial dynamics

et al. 2022

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FMS-like receptor tyrosine kinase 3 (Flt3) expression was reported to increase in the heart in response to pathological stress, but the role of Flt3 activation and its underlying mechanisms remain poorly elucidated. This study was designed to investigate the role of Flt3 activation in sympathetic hyperactivity-induced cardiac hypertrophy and its mechanisms through autophagy and mitochondrial dynamics. In vivo, cardiac hypertrophy was established by subcutaneous injection of isoprenaline (6 mg/kg•day) in C57BL/6 mice for 7 consecutive days.The Flt3-ligand intervention was launched 2 h prior to isoprenaline each day. In vitro, experiments of cardiomyocyte hypertrophy, autophagy, and mitochondrial dynamics were performed in neonatal rat cardiomyocytes (NRCMs). Our results revealed that the expression level of Flt3 protein was significantly increased in the hypertrophic myocardium provoked by isoprenaline administration. Flt3ligand intervention alleviated isoprenaline-induced cardiac oxidative stress, hypertrophy, fibrosis, and contractile dysfunction. Isoprenaline stimulation impaired autophagic flux in hypertrophic mouse hearts, supported by the accumulation of LC3II and P62 proteins, while Flt3-ligand restored the impairment of autophagic flux. Flt3 activation normalized the imbalance of mitochondrial fission and fusion in the hearts of mice evoked by isoprenaline as evidenced by the neutralization of elevated mitochondrial fission markers and reduced mitochondrial fusion markers. In NRCMs, Flt3-ligand treatment attenuated isoprenaline-stimulated hypertrophy, which was abolished by a

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…As for the analysis mitochondrial network in TEM images of mice, we selected 5 images per mouse for assessment (n = 3), with approximately 25 mitochondria per image. 16…”

Section: Transmission Electron Microscopy (Tem)mentioning

confidence: 99%

Section: Mitochondrial Trackingmentioning

confidence: 99%

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Activation of FMS ‐like tyrosine kinase 3 protects against isoprenaline‐induced cardiac hypertrophy by improving autophagy and mitochondrial dynamics

et al. 2022

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“…Mitophagy can be visualized in vivo using mitophagy-associated fluorescence proteins, such as mt-keima, mito-QC, and RFP/GFP-LC3 [ 249 ]. Colocalization of mitochondria (marked by MitoTracker or mitochondrial-specific fluorescent antibody) and autophagosomes (indicated by GFP-LC3) or lysosomes (dansylcadaverine, LysoTracker, or lysosome-specific fluorescent antibody) under fluorescence microscope, as well as immunoblotting of Parkin, LC3II/I, ubiquitin, Atg5, Beclin1, and p62 are widely used methods for mitophagy detection in vitro [ 247 , 250 , 251 , 252 , 253 ]. Based on these methods, sunitinib and sorafenib were shown to impair mitophagy via inhibition of ribosomal S6 kinase and AMPK.…”

Section: Main Properties Of Mitochondria and Drug-induced Mitochondri...mentioning

confidence: 99%

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

Tang

Wang

et al. 2022

Pharmaceutics

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Drug-induced cardiotoxicity not only leads to the attrition of drugs during development, but also contributes to the high morbidity and mortality rates of cardiovascular diseases. Comprehensive testing for proarrhythmic risks of drugs has been applied in preclinical cardiac safety assessment for over 15 years. However, other mechanisms of cardiac toxicity have not received such attention. Of them, mitochondrial impairment is a common form of cardiotoxicity and is known to account for over half of cardiovascular adverse-event-related black box warnings imposed by the U.S. Food and Drug Administration. Although it has been studied in great depth, mitochondrial toxicity assessment has not yet been incorporated into routine safety tests for cardiotoxicity at the preclinical stage. This review discusses the main characteristics of mitochondria in cardiomyocytes, drug-induced mitochondrial toxicities, and high-throughput screening strategies for cardiomyocytes, as well as their proposed integration into preclinical safety pharmacology. We emphasize the advantages of using adult human primary cardiomyocytes for the evaluation of mitochondrial morphology and function, and the need for a novel cardiac safety testing platform integrating mitochondrial toxicity and proarrhythmic risk assessments in cardiac safety evaluation.

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Adenine base editor corrected ADPKD point mutations in hiPSCs and kidney organoids

Wang,

Qiu,

Zhang

et al. 2024

Adv. Biotechnol.

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Autosomal dominant polycystic kidney disease (ADPKD) is a dominant genetic disorder caused primarily by mutations in the PKD1 gene, resulting in the formation of numerous cysts and eventually kidney failure. However, there are currently no gene therapy studies aimed at correcting PKD1 gene mutations. In this study, we identified two mutation sites associated with ADPKD, c.1198 (C > T) and c.8311 (G > A), which could potentially be corrected by adenine base editor (ABE). The correction efficiencies of different ABE variants were tested using the HEK293T-PKD1 c.1198 (C > T) and HEK293T-PKD1 c.8311 (G > A) reporter cell lines. We then generated induced pluripotent stem cells (iPSCsmut/WT) from the peripheral blood mononuclear cells (PBMCs) of the heterozygous patient to develop a disease cell model. Since the iPSCsmut/WT did not exhibit a typical disease phenotype in stem cell status, differentiation into kidney organoids in vitro led to the expression of kidney organ-specific marker proteins. Stimulation of cAMP signaling with forskolin resulted in cystic expansion of renal epithelial tissue in iPSCmut/WT-derived kidney organoids, resembling the cystic phenotype observed in ADPKD patients. However, kidney organoids differentiated from ABE-corrected iPSCs did not display the cystic phenotype. Furthermore, we used a dual AAV split-ABEmax system as a therapeutic strategy and achieved an average editing efficiency of approximately 6.56% in kidney organoids. Overall, this study provides a framework for gene therapy targeting ADPKD through ABE single-base editing, offering promising prospects for future therapeutic interventions.

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Polycystin‐1 regulates cardiomyocyte mitophagy

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 12 publications

References 54 publications

Activation of FMS ‐like tyrosine kinase 3 protects against isoprenaline‐induced cardiac hypertrophy by improving autophagy and mitochondrial dynamics

Activation of FMS ‐like tyrosine kinase 3 protects against isoprenaline‐induced cardiac hypertrophy by improving autophagy and mitochondrial dynamics

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

Adenine base editor corrected ADPKD point mutations in hiPSCs and kidney organoids

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