Refine
Has Fulltext
- yes (12)
Is part of the Bibliography
- yes (12)
Document Type
- Journal article (11)
- Doctoral Thesis (1)
Keywords
- blood vessel (2)
- CXCL12-abundant reticular (CAR)-cells (1)
- Developmental biology (1)
- INM (1)
- Kernhülle (1)
- LEM Domäne (1)
- LEM domain (1)
- Molekularbiologie (1)
- OXPHOS (1)
- Proteine (1)
- ROS (1)
- SARS-CoV-2 (1)
- Stem cells (1)
- TGFβ signaling (1)
- Taufliege (1)
- Y-gastric bypass (1)
- age-related macular degeneration (1)
- aging (1)
- angiogenesis (1)
- animal models (1)
- anti‐aging (1)
- aorta ring (1)
- assembloid (1)
- bariatric surgery (1)
- biliopancreatic diversion (1)
- body weight (1)
- brain-retina axis (1)
- cell biology (1)
- contractility (1)
- cotransporter SGLT1 (1)
- cytokines (1)
- diabetic retinopathy (1)
- dilated cardiomyopathy with ataxia (1)
- duodenal jejunal bypass (1)
- electron microscopy (1)
- endothelial cell infection (1)
- extrusion of hiMPC-containing bioinks alginate + collagen type I (1)
- food intake (1)
- genetics (1)
- glucagon like peptide-1 (1)
- gut hormones (1)
- hACE2 (1)
- heart-brain axis (1)
- high contrast (1)
- human iPSC-derived mesodermal cells (hiMPCs) (1)
- human induced pluripotent stem cells (1)
- human neurons (1)
- induced neural stem cells (1)
- induced pluripotent stem cells (1)
- inflammation (1)
- innere Kernmembran (1)
- intestinal glucose (1)
- ischemic stroke (1)
- megakaryocytes (1)
- mesodermal organoid (1)
- metabolism (1)
- microvasculature (1)
- mitochondria (1)
- molecular biology (1)
- mouse (1)
- multilayered vessel wall with intimate, media and adventitia (1)
- myocardial infarction (1)
- neural crest (1)
- neural organoid (1)
- neurotrophins (1)
- nuclear envelope (1)
- organoid (1)
- peripheral nervous system (1)
- reactive oxygen species (1)
- sensory ganglia (1)
- sensory neuron (1)
- serial block face EM (1)
- synapse (1)
- synaptic vesicles (1)
- transmission electron microscopy (1)
- vascular biofabrication (1)
- vascular network and hierarchical organized vessels (1)
- vasculature (1)
- vasculogenesis (1)
Institute
- Institut für Anatomie und Zellbiologie (11)
- Abteilung für Funktionswerkstoffe der Medizin und der Zahnheilkunde (1)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (1)
- Institut für Pharmakologie und Toxikologie (1)
- Institut für Virologie und Immunbiologie (1)
- Julius-von-Sachs-Institut für Biowissenschaften (1)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (1)
- Klinik und Poliklinik für Nuklearmedizin (1)
- Medizinische Klinik und Poliklinik I (1)
- Neurologische Klinik und Poliklinik (1)
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.