Biology subjects

Sossalla, S.

Publications and source records attributed to Sossalla, S..

7 recordsLinked to original sources

bioRxiv2026

AMPK reinforces mitochondrial metabolism and suppresses pathological remodeling in Complex V-deficient cardiomyocytes

TMEM70 variants represent the most common nuclear cause of mitochondrial ATP synthase (Complex V) deficiency and are associated with particularly severe cardiac manifestations. Yet, how TMEM70 deficiency disrupts cardiomyocyte metabolic maturation and function remains poorly understood, in part because suitable human disease models are lacking. Here, we model TMEM70-related Complex V deficiency using CRISPR-engineered human induced pluripotent stem cells differentiated into cardiomyocytes. While TMEM70-deficient pluripotent cells retain mitochondrial function, differentiated cardiomyocytes develop reduced mitochondrial membrane potential, impaired respiratory capacity, and pathological remodeling, revealing a differentiation-dependent failure of metabolic maturation. Chronic activation of AMP-activated protein kinase (AMPK) restores mitochondrial respiratory capacity despite persistent Complex V deficiency. Proteomic and metabolomic analyses reveal that AMPK activation in TMEM70-deficient cardiomyocytes reinforces mitochondrial and fatty-acid metabolism while suppressing pathological structural remodeling, accompanied by improved cardiac function. Together, these findings identify AMPK-dependent metabolic remodeling as a state-dependent mechanism of functional rescue in mitochondrial cardiomyopathy.

cell biology↗

bioRxiv2025

Genomic G quadruplexes regulate mRNA splicing

Genomic G quadruplexes (G4) are non-canonical DNA structures that regulate gene expression primarily through transcriptional control. Here, we uncover that DNA G quadruplexes are critical determinants of pre-mRNA splicing. G4s on the DNA template strand serve as recruiting elements for the RNA-binding proteins SRSF9 and WBP11 in order to facilitate productive splicing of adjacent pre-mRNAs. This process is controlled by protein arginine methyltransferase 5 (PRMT5) that releases SRSF9 and WBP11 from G4s through arginine methylation. Acyl-CoA dehydrogenase very long-chain specific (ACADVL) is a gene highly regulated by this mechanism since targeting G4 stability prevents mis-splicing and restores ACADVL protein levels. In the heart, deletion of Prmt5 recapitulates defective splicing and results in progressive cardiac failure along with loss of ACADVL in mice. Importantly, we find that Acadvl regulation plays a critical role for cardiomyopathy as restoring Acadvl expression in Prmt5 knockout mice prevents cardiac dysfunction. This study establishes an unanticipated fundamental principle by which genomic G quadruplexes act as splicing enhancers of associated pre-mRNAs, and reveals an essential role in cardiac homeostasis.

cell biology↗

bioRxiv2025

Enhanced iPSC-Cardiomyocyte Maturation via Combined 3D-Culture and Metabolic Cues

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) have become an invaluable tool for disease modelling and drug testing. However, while many etiologies of heart failure involve defects in excitation-contraction coupling, mitochondrial energetics or both, iPSC-CM are limited by the developmental immaturity of these processes. Here, we report a combinatorial strategy to enhance the maturation of human iPSC-CM by integrating three-dimensional (3D) spheroid culture conditions with a defined hormone- and fatty acid-enriched maturation medium (MM). A comprehensive analysis of structural, electrophysiological and Ca2+ handling parameters was performed to evaluate cellular and functional maturation. The iPSC-CM generated under these conditions (3D_MM) exhibit many phenotypic characteristics that resemble those of isolated adult human CM, including (i) a rod-shaped morphology, (ii) cardiac ultrastructural features such as aligned myofilaments, unidirectional organized sarcomeres, and the presence of transverse (t)-tubules, (iii) refined action potential (AP) parameters and Ca2+ handling, and (iv) {beta}-adrenergic responsiveness and a positive force-frequency relationship. Compared with long-term (LT) monolayer cultures of 90 days or the individual cues (3D or MM alone), the 3D_MM protocol achieves mostly superior or at the least non-inferior maturation effects. This systematic investigation further demonstrates that while 3D culturing or MM alone improved specific aspects of maturation, only their synergistic combination produced a comprehensive enhancement of key CM processes, such as excitation-contraction coupling and mitochondrial energetics.

cell biology↗

bioRxiv2025

Peroxisome protein import deficiency causes heart failure in mouse and human

Peroxisomes are ubiquitous cellular organelles with potentially vital roles in lipid and reactive oxygen metabolism. The metabolic demands of the heart are substantial; however, the contribution of peroxisomes to cardiac development, health, and their role in heart failure (HF) remain largely unexplored. We developed and examined a mouse and an engineered human myocardium (EHM) model with a deficiency in cardiac peroxisome biogenesis to investigate the role of peroxisomes in cardiac function and pathology. In the EHM, loss of peroxisome protein import and subsequent peroxisomal metabolic impairment trigger mitochondrial damage and compromise cellular respiration and energy production. Peroxisome dysfunction results in incoherent electrical conduction, defective Ca2+-handling, and ultimately presentation of a HF phenotype with pathological force generation. These phenotypes are mirrored in an orthogonal murine model system with defective cardiac peroxisome biogenesis. Preload-dependent deficits in force generation due to insufficient energy supply are eventually fatal. Thus, peroxisomes play an important role in sustaining normal heart operations. Vice versa, peroxisome maintenance is compromised in pressure overload-induced HF, establishing peroxisomes as potential modulators of pathology and targets of therapy.

cell biology↗

bioRxiv2025

A role of extracellular vesicle-mediated inter-organ communication in obesity-related arrhythmia

Obesity contributes to the risk of cardiac arrhythmias, but the exact mechanism remains unclear. Here, we show visceral adipose tissue-derived extracellular vesicles (VAT EVs) from individuals with obesity prolong action potential duration (APD) and impair calcium handling in stem cell-derived cardiomyocytes, in addition to activating fibroblasts and macrophages towards a pro-fibrotic/inflammatory state, thereby creating pro-arrhythmic substrate. Adipose-derived EVs target the heart in obese mice, suggesting the potential for direct communication. Transcriptome-wide genetic association (TWAS) and epigenetic studies anchored on genes differentially expressed in cardiomyocytes, fibroblasts, and macrophages after VAT-EV exposure identified genes significantly associated with QT interval and atrial fibrillation. Finally, as a proof-of-principle, we pharmacologically blocked TRPC3 (a VAT-EV-induced ion channel) in cardiomyocytes, restoring the APD towards normality. This molecular genetic evidence supports an EV-mediated direct communication pathway between adipose tissue and the heart in arrhythmogenesis, offering a new paradigm to identify mediators of cardiovascular disease in obesity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/676027v1_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@114b230org.highwire.dtl.DTLVardef@1be7926org.highwire.dtl.DTLVardef@3d6b0org.highwire.dtl.DTLVardef@3ef15_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation

Atrial fibrillation (AFib) and the risk of its lethal complications are propelled by fibrosis, which induces electrical heterogeneity and gives rise to reentry circuits. Atrial TREM2+ macrophages secrete osteopontin (encoded by Spp1), a matricellular signaling protein that engenders fibrosis and AFib. Here we show that silencing Spp1 in TREM2+ cardiac macrophages with an antibody-siRNA conjugate reduces atrial fibrosis and suppresses AFib in mice, thus offering a new immunotherapy for the most common arrhythmia.

immunology↗

bioRxiv2020

Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients

Cancer therapies have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of cancer. ACT-iPSC-CM generated from individuals with CD20+ B-cell lymphoma cancer who had received high doses of DOX and suffered cardiac dysfunction were observed to be persistently more susceptible to DOX toxicity compared to control-iPSC-CM. ACT-iPSC-CM exhibited increased DOX-dependent disorganized myofilament structure and cell death, as well as higher reactive oxygen species (ROS) compared to controls. Importantly, analysis of engineered heart muscle (EHM) from ACT-iPSC-CM showed an impaired DOX-dependent mechanical functionality. Transcriptome profiles of EHM are in line with a disturbed adjustment to DOX-dependent alteration of Ca2+ homeostasis in ACT-iPSC-CM. Furthermore, genetic variants in different cardiac key regulators were uncovered. In conclusion, we developed the first human iPSC-CM and EHM model of DOX-induced cardiac dysfunction in patients with B-cell lymphoma. Our results suggest that DOX-related stress resulted in decreased contractile activity and finally in heart failure in ACT patients. Brief summaryDevelopment of the first human iPSC-CM model of DOX-induced cardiac dysfunction in patients with aggressive B cell lymphoma and high-dose DOX treatment.

cell biology↗