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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.
The receptor activity-modifying proteins (RAMPs) are ubiquitously expressed membrane proteins that interact with several G protein-coupled receptors (GPCRs), the largest and pharmacologically most important family of cell surface receptors. RAMPs can regulate GPCR function in terms of ligand-binding, G-protein coupling, downstream signaling, trafficking, and recycling. The integrity of their interactions translates to many physiological functions or pathological conditions.
Regardless of numerous reports on its essential importance for cell biology and pivotal role in (patho-)physiology, the molecular mechanism of how RAMPs modulate GPCR activation remained largely elusive.
This work presents new insights that add to the common understanding of the allosteric regulation of receptor activation and will help interpret how accessory proteins - RAMPs - modulate activation dynamics and how this affects the fundamental aspects of cellular signaling. Using a prototypical class B GPCR, the parathyroid hormone 1 receptor (PTH1R) in the form of advanced genetically encoded optical biosensors, I examined RAMP's impact on the PTH1R activation and signaling in intact cells. A panel of single-cell FRET and confocal microscopy experiments as well canonical and non-canonical functional assays were performed to get a holistic picture of the signaling initiation and transduction of that clinically and therapeutically relevant GPCR. Finally, structural modeling was performed to add molecular mechanistic details to that novel art of modulation.
I describe here that RAMP2 acts as a specific allosteric modulator of PTH1R, shifting PTH1R to a unique pre-activated state that permits faster activation in a ligand-specific manner. Moreover, RAMP2 modulates PTH1R downstream signaling in an agonist-dependent manner, most notably increasing the PTH-mediated Gi3 signaling sensitivity and kinetics of cAMP accumulation. Additionally, RAMP2 increases PTH- and PTHrP-triggered β-arrestin2 recruitment to PTH1R and modulates cytosolic ERK1/2 phosphorylation. Structural homology modeling shows that structural motifs governing GPCR-RAMP interaction originate in allosteric hotspots and rationalize functional modulation. Moreover, to interpret the broader role of RAMP's modulation in GPCRs pharmacology, different fluorescent tools to investigate RAMP's spatial organization were developed, and novel conformational biosensors for class B GPCRs were engineered. Lastly, a high throughput assay is proposed and prototyped to expand the repertoire of RAMPs or other membrane protein interactors.
These data uncover the critical role of RAMPs in GPCR activation and signaling and set up a novel platform for studying GPCR modulation. Furthermore, these insights may provide a new venue for precise modulation of GPCR
function and advanced drug design.
Changes in sugar composition occur continuously in plant tissues at different developmental stages. Tuber dormancy induction, stability, and breaking are very critical developmental transitions in yam crop production. Prolonged tuber dormancy after physiological maturity has constituted a great challenge in yam genetic improvement and productivity. In the present study, biochemical profiling of non-structural sugar in yam tubers during dormancy was performed to determine the role of non-structural sugar in yam tuber dormancy regulation. Two genotypes of the white yam species, one local genotype (Obiaoturugo) and one improved genotype (TDr1100873), were used for this study. Tubers were sampled at 42, 56, 87, 101, 115, and 143 days after physiological maturity (DAPM). Obiaoturugo exhibited a short dormant phenotype and sprouted at 101-DAPM, whereas TDr1100873 exhibited a long dormant phenotype and sprouted at 143-DAPM. Significant metabolic changes were observed in non-structural sugar parameters, dry matter, and moisture content in Obiaoturugo from 56-DAPM, whereas in TDr1100873, significant metabolic changes were observed from 101-DAPM. It was observed that the onset of these metabolic changes occurred at a point when the tubers of both genotypes exhibited a dry matter content of 60%, indicating that a dry matter content of 60% might be a critical threshold for white yam tuber sprouting. Non-reducing sugars increased by 9–10-fold during sprouting in both genotypes, which indicates their key role in tuber dormancy regulation in white yam. This result implicates that some key sugar metabolites can be targeted for dormancy manipulation of the yam crop.
Pyrrolizidine alkaloids (PAs) are secondary plant metabolites, which can be found as contaminant in various foods and herbal products. Several PAs can cause hepatotoxicity and liver cancer via damaging hepatic sinusoidal endothelial cells (HSECs) after hepatic metabolization. HSECs themselves do not express the required metabolic enzymes for activation of PAs. Here we applied a co-culture model to mimic the in vivo hepatic environment and to study PA-induced effects on not metabolically active neighbour cells. In this co-culture model, bioactivation of PA was enabled by metabolically capable human hepatoma cells HepG2, which excrete the toxic and mutagenic pyrrole metabolites. The human cervical epithelial HeLa cells tagged with H2B-GFP were utilized as non-metabolically active neighbours because they can be identified easily based on their green fluorescence in the co-culture. The PAs europine, riddelliine and lasiocarpine induced micronuclei in HepG2 cells, and in HeLa H2B-GFP cells co-cultured with HepG2 cells, but not in HeLa H2B-GFP cells cultured alone. Metabolic inhibition of cytochrome P450 enzymes with ketoconazole abrogated micronucleus formation. The efflux transporter inhibitors verapamil and benzbromarone reduced micronucleus formation in the co-culture model. Furthermore, mitotic disturbances as an additional genotoxic mechanism of action were observed in HepG2 cells and in HeLa H2B-GFP cells co-cultured with HepG2 cells, but not in HeLa H2B-GFP cells cultured alone. Overall, we were able to show that PAs were activated by HepG2 cells and the metabolites induced genomic damage in co-cultured HeLa cells.
Complement 1q/tumor necrosis factor-related proteins (CTRPs): structure, receptors and signaling
(2023)
Adiponectin and the other 15 members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of an N-terminal variable domain followed by a stalk region and a characteristic C-terminal trimerizing globular C1q (gC1q) domain originally identified in the subunits of the complement protein C1q. We performed a basic PubMed literature search for articles mentioning the various CTRPs or their receptors in the abstract or title. In this narrative review, we briefly summarize the biology of CTRPs and focus then on the structure, receptors and major signaling pathways of CTRPs. Analyses of CTRP knockout mice and CTRP transgenic mice gave overwhelming evidence for the relevance of the anti-inflammatory and insulin-sensitizing effects of CTRPs in autoimmune diseases, obesity, atherosclerosis and cardiac dysfunction. CTRPs form homo- and heterotypic trimers and oligomers which can have different activities. The receptors of some CTRPs are unknown and some receptors are redundantly targeted by several CTRPs. The way in which CTRPs activate their receptors to trigger downstream signaling pathways is largely unknown. CTRPs and their receptors are considered as promising therapeutic targets but their translational usage is still hampered by the limited knowledge of CTRP redundancy and CTRP signal transduction.
The US National Research Council (NRC) report "Toxicity Testing in the 21st Century: A Vision and a strategy (Tox21)", published in 2007, calls for a complete paradigm shift in tox-icity testing. A central aspect of the proposed strategy includes the transition from apical end-points in in vivo studies to more mechanistically based in vitro tests. To support and facilitate the transition and paradigm shift in toxicity testing, the Adverse Outcome Pathway (AOP) concept is widely recognized as a pragmatic tool. As case studies, the AOP concept was ap-plied in this work to develop AOPs for proximal tubule injuries initiated by Receptor-mediated endocytosis and lysosomal overload and Inhibition of mtDNA polymerase-. These AOPs were used as a mechanistic basis for the development of in vitro assays for each key event (KE). To experimentally support the developed in vitro assays, proximal tubule cells from rat (NRK-52E) and human (RPTEC/TERT1) were treated with model compounds. To measure the dis-turbance of lysosomal function in the AOP – Receptor-mediated endocytosis and lysosomal overload, polymyxin antibiotics (polymyxin B, colistin, polymyxin B nonapeptide) were used as model compounds. Altered expression of lysosomal associated membrane protein 1/2 (LAMP-1/2) (KE1) and cathepsin D release from lysosomes (KE2) were determined by im-munofluorescence, while cytotoxicity (KE3) was measured using the CellTiter-Glo® cell via-bility assay. Importantly, significant differences in polymyxin uptake and susceptibility be-tween cell lines were observed, underlining the importance of in vitro biokinetics to determine an appropriate in vitro point of departure (PoD) for risk assessment. Compared to the in vivo situation, distinct expression of relevant transporters such as megalin and cubilin on mRNA and protein level in the used cell lines (RPTEC/TERT1 and NRK-52E) could not be con-firmed, making integration of quantitative in vitro to in vivo extrapolations (QIVIVE) neces-sary. Integration of QIVIVE by project partners of the University of Utrecht showed an im-provement in the modelled biokinetic data for polymyxin B. To assess the first key event, (KE1) Depletion of mitochondrial DNA, in the AOP – Inhibition of mtDNA polymerase-, a RT-qPCR method was used to determine the mtDNA copy number in cells treated with mod-el compounds (adefovir, cidofovir, tenofovir, adefovir dipivoxil, tenofovir disoproxil fumarate). Mitochondrial toxicity (KE2) was measured by project partners using the high-content imaging technique and MitoTracker® whereas cytotoxicity (KE3) was determined by CellTiter-Glo® cell viability assay. In contrast to the mechanistic hypothesis underlying the AOP – Inhibition of mtDNA polymerase-, treatment with model compounds for 24 h resulted in an increase rather than a decrease in mtDNA copy number (KE1). Only minor effects on mitochondrial toxicity (KE2) and cytotoxicity (KE3) were observed. Treatment of RPT-EC/TERT1 cells for 14 days showed only a slight decrease in mtDNA copy number after treatment with adefovir dipivoxil and tenofovir disoproxil fumarate, underscoring some of the limitations of short-term in vitro systems. To obtain a first estimation for risk assessment based on in vitro data, potential points of departure (PoD) for each KE were calculated from the obtained in vitro data. The most common PoDs were calculated such as the effect concentra-tion at which 10 % or 20_% effect was measured (EC10, EC20), the highest no observed effect concentration (NOEC), the lowest observed effect concentration (LOEC), the benchmark 10 % (lower / upper) concentrations (BMC10, BMCL10, BMCU10) and a modelled non-toxic con-centration (NtC). These PoDs were then compared with serum and tissue concentrations de-termined from in vivo studies after treatment with therapeutic / supratherapeutic doses of the respective drugs in order to obtain a first estimate of risk based on in vitro data. In addition, AOPs were used to test whether the quantitative key event relationships between key events allow prediction of downstream effects and effects on the adverse outcome (AO) based on measurements of an early key event. Predictions of cytotoxicity from the mathematical rela-tionships showed good concordance with measured cytotoxicity after treatment with colistin and polymyxin b nonapeptide. The work also revealed uncertainties and limitations of the ap-plied strategy, which have a significant impact on the prediction and on a risk assessment based on in vitro results.
Targeting the intrinsic metabolism of immune or tumor cells is a therapeutic strategy in autoimmunity, chronic inflammation or cancer. Metabolite repair enzymes may represent an alternative target class for selective metabolic inhibition, but pharmacological tools to test this concept are needed. Here, we demonstrate that phosphoglycolate phosphatase (PGP), a prototypical metabolite repair enzyme in glycolysis, is a pharmacologically actionable target. Using a combination of small molecule screening, protein crystallography, molecular dynamics simulations and NMR metabolomics, we discover and analyze a compound (CP1) that inhibits PGP with high selectivity and submicromolar potency. CP1 locks the phosphatase in a catalytically inactive conformation, dampens glycolytic flux, and phenocopies effects of cellular PGP-deficiency. This study provides key insights into effective and precise PGP targeting, at the same time validating an allosteric approach to control glycolysis that could advance discoveries of innovative therapeutic candidates.
In line with recent OECD activities on the use of AOPs in developing Integrated Approaches to Testing and Assessment (IATAs), it is expected that systematic mapping of AOPs leading to systemic toxicity may provide a mechanistic framework for the development and implementation of mechanism-based in vitro endpoints. These may form part of an integrated testing strategy to reduce the need for repeated dose toxicity studies. Focusing on kidney and in particular the proximal tubule epithelium as a key target site of chemical-induced injury, the overall aim of this work is to contribute to building a network of AOPs leading to nephrotoxicity. Current mechanistic understanding of kidney injury initiated by 1) inhibition of mitochondrial DNA polymerase γ (mtDNA Polγ), 2) receptor mediated endocytosis and lysosomal overload, and 3) covalent protein binding, which all present fairly well established, common mechanisms by which certain chemicals or drugs may cause nephrotoxicity, is presented and systematically captured in a formal description of AOPs in line with the OECD AOP development programme and in accordance with the harmonized terminology provided by the Collaborative Adverse Outcome Pathway Wiki. The relative level of confidence in the established AOPs is assessed based on evolved Bradford-Hill weight of evidence considerations of biological plausibility, essentiality and empirical support (temporal and dose-response concordance).
The sodium channel Na\(_{v}\)1.8, encoded by SCN10A, is reported to contribute to arrhythmogenesis by inducing the late I\(_{Na}\) and thereby enhanced persistent Na\(^{+}\) current. However, its exact electrophysiological role in cardiomyocytes remains unclear. Here, we generated induced pluripotent stem cells (iPSCs) with a homozygous SCN10A knock-out from a healthy iPSC line by CRISPR Cas9 genome editing. The edited iPSCs maintained full pluripotency, genomic integrity, and spontaneous in vitro differentiation capacity. The iPSCs are able to differentiate into iPSC-cardiomyocytes, hence making it possible to investigate the role of Na\(_{v}\)1.8 in the heart.
In the heart the β\(_1\)-adrenergic receptor (AR) and the β\(_2\)-AR, two prototypical G protein-coupled receptors (GPCRs), are both activated by the same hormones, namely adrenaline and noradrenaline. Both receptors couple to stimulatory G\(_s\) proteins, mediate an increase in cyclic adenosine monophosphate (cAMP) and influence the contractility and frequency of the heart upon stimulation. However, activation of the β\(_1\)-AR, not the β\(_2\)-AR, lead to other additional effects, such as changes in gene transcription resulting in cardiac hypertrophy, leading to speculations on how distinct effects can arise from receptors coupled to the same downstream signaling pathway.
In this thesis the question of whether this distinct behavior may originate from a differential localization of these two receptors in adult cardiomyocytes is addressed. Therefore, fluorescence spectroscopy tools are developed and implemented in order to elucidate the presence and dynamics of these endogenous receptors at the outer plasma membrane as well as on the T-tubular network of intact adult cardiomyocytes. This allows the visualization of confined localization and diffusion of the β\(_2\)-AR to the T-tubular network at endogenous expression. In contrast, the β\(_1\)-AR is found diffusing at both the outer plasma membrane and the T-tubules. Upon overexpression of the β\(_2\)-AR in adult transgenic cardiomyocytes, the receptors experience a loss of this compartmentalization and are also found at the cell surface. These data suggest that distinct signaling and functional effects can be controlled by specific cell surface targeting of the receptor subtypes.
The tools at the basis of this thesis work are a fluorescent adrenergic antagonist in combination of fluorescence fluctuation spectroscopy to monitor the localization and dynamics of the lowly expressed adrenergic receptors. Along the way to optimizing these approaches, I worked on combining widefield and confocal imaging in one setup, as well as implementing a stable autofocus mechanism using electrically tunable lenses.