Biology subjects

Sandmann, C.

Publications and source records attributed to Sandmann, C..

6 recordsLinked to original sources

bioRxiv2025

LINC01503-MP is a Mitochondrial Microprotein That Promotes Cell Proliferation and Oxidative Metabolism.

Long non-coding RNAs (lncRNAs) are well-established as key regulators of gene expression. However, emerging evidence reveals that some lncRNAs can also encode functional microproteins. In this study, we report the identification of an evolutionarily young microprotein encoded by LINC01503, expressed across several human tissues. This microprotein, designated as LINC01503-MP, localises to the mitochondria and exerts a proliferative effect on HCT116 colorectal cancer (CRC) cells. Functional studies reveal that LINC01503-MP regulates mitochondrial oxygen consumption rate, linking its activity to enhanced metabolic functions and cell proliferation. Interactome analyses identified multiple mitochondrial metabolism-related proteins as potential interaction partners. Our findings show that LINC01503-MP plays a role in the proliferative phenotype associated with LINC01503 upregulation in CRC, suggesting the functional significance of evolutionarily young, lncRNA-derived microproteins in cancer progression.

molecular biology↗

bioRxiv2025

A cross-species multimodal database of gene expression in cardiac hypertrophy

Changes in gene expression determine the pathophysiological response of the heart during increased workload and biomechanical stress.1,2 Understanding the complex gene expression regulation during physiological and pathological stress provides insight into mechanisms that mediate the transition from cardiac hypertrophy to heart failure. We curated and generated a multi-omics database of cardiac hypertrophy and heart failure and exemplified its usage by evaluating the regulation of UCK2, a gene that belongs to a conserved cardiomyocyte hypertrophy gene expression signature with unknown function in heart disease. To provide the community with simple access to the database, we developed CHEERIO (Cardiac HypErtrophy gEne expRessIOn Database), a free and easy-to-use interactive web application to explore rodent and human gene expression during early, late, physiological and pathological cardiac hypertrophy, as well as heart failure at transcriptome, translatome, proteome, bulk and single-cell resolution. CHEERIO is freely available at https://voelkerslab.shinyapps.io/CHEERIO/.

physiology↗

bioRxiv2024

Development of a protein synthesis network at the sarco/endoplasmic reticulum in adult cardiac myocytes

IntroductionThe endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins, which constitute a large fraction of the total protein output of a mammalian cell. Striated muscle cells contain a specialized membrane system known as the sarcoplasmic reticulum (SR) that controls calcium homeoastasis and contraction, however the biochemical and physiological relationship between the ER and SR and how both compartments participate in protein synthesis remains incompletely understood. MethodsProtein quantification and imaging of selected marker proteins for ER and SR functions was performed to characterize the relationship of the ER and SR and its individual involvement in protein synthesis in neonatal and adult cardiac myocytes. Superresolution microscopy was used to examine the interaction of ribosomes and the SR in adult cardiac myocytes. ResultsQuantification of ER and SR-associated proteins of isolated ventricular cardiac myocytes showed that relative expression of ER/SR resident protein quality elements, as well as relative ribosome levels are decreased in adult cells, whereas SR-associated Ca2+ handling proteins increase. Immunocytoflourescence revealed that the membrane compartment that exists in early postpartum resembles mostly the ER and decreases in postnatal development. The SR is the main membrane network that exists in the adult cardiac myocytes, replacing the ER, in all but the perinuclear region. Immunocytoflourescence staining further indicated that both networks perform overlapping but distinct, specialized functions, such as localization of excitation-contraction coupling exclusively to the SR or initiation of secretion via the classical secretory pathway mainly from the ER. Ribosomes and mRNA were localized both in close proximity to the ER and the SR of adult ventricular cardiac myocytes. Superresolution microscopy confirmed that both the ER as well as the developed SR bind ribosomes and are direct sites of protein synthesis and protein homeostasis in adult cardiac myocytes. ConclusionOur findings suggest molecular differentiation and structural organization of the ER/SR in cardiac muscle development, resulting in the development of a protein synthesis network at the sarco/endoplasmic reticulum in adult cardiac myocytes.

cell biology↗

bioRxiv2022

Transient inhibition of translation improves long-term cardiac function after ischemia/reperfusion by attenuating the inflammatory response

RationaleRapid reperfusion is the most effective treatment for attenuating cardiac injury caused by myocardial ischemia. Yet, reperfusion itself elicits damage to the myocardium through incompletely understood mechanisms, known as ischemia/reperfusion (I/R) injury. The myocardium adapts to I/R by changes in gene expression, which determines the cellular response to reperfusion. Protein translation is a key component of gene expression. However, it is unknown how regulation of translation contributes to cardiac gene expression in response to reperfusion and whether it can be targeted to mitigate I/R injury. MethodsTo examine translation and its impact on gene expression in response to I/R we assessed protein synthesis at different timepoints after ischemia and reperfusion in vitro and in vivo. Pharmacological inhibitors were used to dissect the underlying molecular mechanisms of translational control. Transient inhibition of protein synthesis was undertaken to decipher the effects of the translational response to reperfusion on cardiac function and inflammation. Cell-type-specific ribosome profiling was performed in mice subjected to I/R to determine the impact of translation on the regulation of gene expression in cardiomyocytes. ResultsReperfusion increased translation rates from a previously suppressed state during ischemia in cardiomyocytes, which was associated with the induction of cell death. In vivo, I/R resulted in strong activation of translation in the myocardial border zone. Detailed analysis revealed that the upregulation of translation is mediated by eIF4F complex formation, which was specifically mediated by the mTORC1-4EBP1-eIF4F axis. Short-term pharmacological inhibition of eIF4F complex formation by 4EGI-1 or rapamycin, respectively, attenuated translation, reduced infarct size and improved long-term cardiac function after myocardial infarction. Cardiomyocyte-specific ribosome profiling identified that reperfusion damage increased translation of mRNA networks in cardiomyocytes associated with cardiac inflammation and cell infiltration. Transient inhibition of the mTORC1-4EBP1-eIF4F axis decreased the expression of proinflammatory transcripts such as Ccl2, thereby reducing Ly6Chi monocyte infiltration and myocardial inflammation. ConclusionsMyocardial reperfusion induces protein synthesis in the border zone which contributes to I/R injury by rapidly translating a specific maladaptive mRNA network that mediates immune cell infiltration and inflammation. Transient inhibition of the mTORC1-4EBP1-eIF4F signaling axis during reperfusion attenuates this proinflammatory translational response, protects against I/R injury and improves long-term cardiac function after myocardial infarction. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIThis is the first study to investigate the impact of translational regulation on cardiomyocyte gene expression in response to myocardial ischemia/reperfusion. C_LIO_LIWe show that translation regulates approximately two-thirds of differentially expressed genes in cardiomyocytes after ischemia/reperfusion, including many involved in inflammation and immune cell infiltration. C_LIO_LIThe translational response to ischemia/reperfusion is regulated by the mTORC1-4EBP1-eIF4F axis, which determines pro-inflammatory monocyte infiltration via control of the expression of the chemokine Ccl2. C_LI What Are the Clinical Implications?O_LICurrently, there are no specific therapies to prevent ischemia/reperfusion injury, which is mediated, at least in part, by a maladaptive inflammatory response. C_LIO_LIA translationally controlled network regulated by the mTORC1-4EBP1-eIF4F axis can be targeted by a short-term pharmacological intervention to attenuate the inflammatory response and improve cardiac function after ischemia/reperfusion in mice. C_LIO_LIThis study supports the emerging concept of selectively inhibiting maladaptive elements of the inflammatory response to improve outcome in patients after myocardial infarction; in addition, it provides a mechanistic basis for the currently ongoing CLEVER-ACS trial. C_LI

molecular biology↗

bioRxiv2021

Age-related decline of the unfolded protein response in the heart promotes protein misfolding and cardiac pathology

Cardiac myocyte death during heart failure is particularly detrimental, given that cardiac muscle exhibits limited regenerative potential. Protein aggregation was previously observed in end-stage heart failure, suggesting protein-misfolding in cardiac myocytes as a contributor to the disease process. However, the relationship between protein-misfolding, cardiac myocyte death, and myocardial dysfunction is yet to be clearly established. Here, we showed that protein synthesis and the unfolded protein response (UPR) declined as a function of mammalian postnatal development, especially in tissues with low mitotic activity, such as the heart. A deeper examination in animals models showed that compared to neonatal cardiac myocytes, adult cardiac myocytes expressed lower levels of the adaptive UPR transcription factor, ATF6, as well as lower levels of numerous ATF6-regulated genes, which was associated with susceptibility to ER stress-induced cell death. Further reduction of the ATF6-dependent gene program in ATF6 knock-out mice led to the accumulation of misfolded proteins in the myocardium and impaired myocardial function in response to cardiac stress, indicating that ATF6 plays a critical adaptive role in the setting of cardiac disease. Thus, strategies to increase ATF6 aimed at balancing proteostasis in cardiac myocytes might be a fruitful avenue for the development of novel therapies for heart disease and other age-associated diseases. HighlightsO_LIThe unfolded protein response (UPR) declines as a function of age in adult mammalian tissues with low mitotic activity, such as the heart C_LIO_LIDecreases in the UPR in adult cardiac myocytes is associated with impaired survival during ER stress C_LIO_LIATF6 loss of function in adult hearts increases protein misfolding and cardiac disfunction during stress C_LI

molecular biology↗

bioRxiv2020

Muscle specific translational control of Cand2 by mTORC1 regulates adverse cardiac remodeling

The mechanistic target of rapamycin (mTOR) is a key regulator of pathological remodeling in the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of mTOR in cardiomyocytes is protective, however, a detailed role of mTOR in translational regulation of specific mRNA networks in the diseased heart is largely unknown. A cardiomyocyte genome-wide sequencing approach was used to define mTOR-dependent post-transcriptional gene expression control at the level of mRNA translation. This approach identified the muscle-specific protein Cullin-associated NEDD8-dissociated protein 2 (Cand2) as a translationally upregulated gene, dependent on the activity of mTOR. Deletion of Cand2 protects the myocardium against pathological remodeling. Mechanistically, we found that Cand2 links mTOR signaling to pathological cell growth by increasing Grk5 protein expression. Our data suggest that cell-type-specific targeting of mTOR might have therapeutic value for adverse pathological cardiac remodeling.

molecular biology↗