Filtern
Volltext vorhanden
- ja (16)
Gehört zur Bibliographie
- ja (16)
Dokumenttyp
Sprache
- Englisch (16)
Schlagworte
- positron emission tomography (4)
- Positronen-Emissions-Tomografie (3)
- sympathetic nervous system (3)
- 11C-HED (2)
- PET (2)
- Stammzelle (2)
- ageing (2)
- cardiomyocytes (2)
- fatty acid (2)
- hiPSC-CM (2)
- induced pluripotent stem cells (2)
- norepinephrine transporter (2)
- stem cell therapy (2)
- tracer (2)
- 11C-Hydroxyephedrine (1)
- 18F-LMI1195 (1)
- Alzheimer’s disease (1)
- HMDP hydroxymethylene diphosphonate (1)
- MRI (1)
- Myocardial-perfusion SPECT (1)
- OXPHOS (1)
- ROS (1)
- SPECT Scanner (1)
- Sodium-Glucose Cotransporters (SGLTs) (1)
- T-shaped π-π stacking (1)
- T-shaped π–π stacking (1)
- amyloid-β (Aβ) (1)
- biomarkers (1)
- butyrylcholinesterase (1)
- carbamate (1)
- cardiac innervation imaging (1)
- cardiac sympathetic nervous system (1)
- cell biology (1)
- computational biology and bioinformatics (1)
- contractility (1)
- diabetes (1)
- dilated cardiomyopathy with ataxia (1)
- ejection fraction (1)
- enzyme kinetics (1)
- fluorine-18 (1)
- genetics (1)
- heart failure (1)
- hydroxyephedrine (1)
- left-ventricular function (1)
- machine learning (1)
- medium-sized animals (1)
- metabolism (1)
- mitochondria (1)
- molecular biology (1)
- molecular medicine (1)
- moycardial sympathetic innervation (1)
- myocardial sympathetic innervation imaging (1)
- neurology (1)
- nonhuman primates (1)
- performance (1)
- phaeochromocytoma (1)
- quality (1)
- radiotracer kinetics (1)
- radiotracers (1)
- rats (1)
- scanner (1)
- skeletal (1)
- small animal SPECT (1)
- stem cells (1)
- stem-cell research (1)
- storage vesicle turnover (1)
- structure–activity relationships (1)
Institut
- Klinik und Poliklinik für Nuklearmedizin (16)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (5)
- Institut für Pharmazie und Lebensmittelchemie (4)
- Institut für Anatomie und Zellbiologie (3)
- Institut für Pharmakologie und Toxikologie (1)
- Institut für diagnostische und interventionelle Radiologie (Institut für Röntgendiagnostik) (1)
- Medizinische Klinik und Poliklinik I (1)
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine (3)
- Department of Biomedical Imaging, National Cerebral and Cardiovascular Research Center, Suita, Japan (2)
- Division of Medical Technology and Science, Department of Medical Physics and Engineering, Course of Health Science, Osaka University Graduate School of Medicine, Suita Japan (2)
- Institut for Molecular Biology and CMBI, Department of Genomics, Stem Cell Biology and Regenerative Medicine, Leopold-Franzens-University Innsbruck, Innsbruck, Austria (2)
- Johns Hopkins School of Medicine, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD, USA (2)
EU-Projektnummer / Contract (GA) number
- 701983 (5)
Highlights
• Loss of DNAJC19's DnaJ domain disrupts cardiac mitochondrial structure, leading to abnormal cristae formation in iPSC-CMs.
• Impaired mitochondrial structures lead to an increased mitochondrial respiration, ROS and an elevated membrane potential.
• Mutant iPSC-CMs show sarcomere dysfunction and a trend to more arrhythmias, resembling DCMA-associated cardiomyopathy.
Background
Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy.
Methods
We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca\(^{2+}\) kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tv\(_{HeLa}\)).
Results
Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca\(^{2+}\) concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation.
Conclusions
Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca\(^{2+}\) kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.