Browsing by Author "Seebohm, Guiscard"

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    Doxorubicin induced senescence affects the integrity of the inner mitochondrial membrane in human iPS derived cardiomyocytes and primary rat cardiomyocytes
    (ELSEVIER, 2022) Morris, Silke; Molina-Riquelme, Isidora; Barrientos, Gonzalo; Bravo, Francisco; Aedo, Geraldine; Gomez, Wileidy; Psathaki, Katherina; Peischard, Stefan; Seebohm, Guiscard; Eisner, Veronica; Busch, Karin B.
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    Inner mitochondrial membrane structure and fusion dynamics are altered in senescent human iPSC-derived and primary rat cardiomyocytes
    (Elsevier B.V., 2023) Morris, Silke; Busch, Karin B.; Molina Riquelme, Isidora; Barrientos, Gonzalo; Bravo, Francisco; Aedo, Geraldine; Gómez, Wileidy; Lagos, Daniel; Eisner Sagues Veronica Raquel; Verdejo, Hugo; Peischard, Stefan; Seebohm, Guiscard; Psathaki, Olympia E.
    Dysfunction of the aging heart is a major cause of death in the human population. Amongst other tasks, mitochondria are pivotal to supply the working heart with ATP. The mitochondrial inner membrane (IMM) ultrastructure is tailored to meet these demands and to provide nano-compartments for specific tasks. Thus, function and morphology are closely coupled. Senescent cardiomyocytes from the mouse heart display alterations of the inner mitochondrial membrane. To study the relation between inner mitochondrial membrane architecture, dynamics and function is hardly possible in living organisms. Here, we present two cardiomyocyte senescence cell models that allow in cellular studies of mitochondrial performance. We show that doxorubicin treatment transforms human iPSC-derived cardiomyocytes and rat neonatal cardiomyocytes in an aged phenotype. The treated cardiomyocytes display double-strand breaks in the nDNA, have ?-galactosidase activity, possess enlarged nuclei, and show p21 upregulation. Most importantly, they also display a compromised inner mitochondrial structure. This prompted us to test whether the dynamics of the inner membrane was also altered. We found that the exchange of IMM components after organelle fusion was faster in doxorubicin-treated cells than in control cells, with no change in mitochondrial fusion dynamics at the meso-scale. Such altered IMM morphology and dynamics may have important implications for local OXPHOS protein organization, exchange of damaged components, and eventually the mitochondrial bioenergetics function of the aged cardiomyocyte.
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    Virus-induced inhibition of cardiac pacemaker channel HCN4 triggers bradycardia in human-induced stem cell system
    (SPRINGER BASEL AG, 2022) Peischard, Stefan; Moeller, Melina; Disse, Paul; Huyen Tran Ho; Verkerk, Arie O.; Strutz-Seebohm, Nathalie; Budde, Thomas; Meuth, Sven G.; Schweizer, Patrick A.; Morris, Silke; Mucher, Lena; Eisner, Veronica; Thomas, Dierk; Klingel, Karin; Busch, Karin; Seebohm, Guiscard
    The enterovirus Coxsackievirus B3 (CVB3) is known to be a major source for the development of cardiac dysfunctions like viral myocarditis (VMC) and dilatative cardiomyopathy (DCM), but also results in bradycardia and fatal cardiac arrest. Besides clinical reports on bradycardia and sudden cardiac death, very little is known about the influence of CVB3 on the activity of human cardiac pacemaker cells. Here, we address this issue using the first human induced pluripotent stem cell (hiPSC)-derived pacemaker-like cells, in which the expression of a transgenic non-infectious variant of CVB3 can be controlled dose- and time-dependently. We found that CVB3 drastically changed hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) distribution and function in hiPSC-derived pacemaker-like tissue. In addition, using HCN4 cell expression systems, we found that HCN4 currents were decreased with altered voltage dependency of activation when CVB3 was expressed. Increased autophagosome formation and autophagosomal HCN4 insertion was observed in hiPSC-derived pacemaker-like cells under CVB3 expression as well. Individual effects of single, non-structural CVB3 proteins were analyzed and demonstrated that CVB3 proteins 2C and 3A had the most robust effect on HCN4 activity. Treatment of cells with the Rab7 inhibitor CID 106770 or the CVB3-3A inhibitor GW5074 led to the recovery of the cytoplasmatic HCN4 accumulation into a healthy appearing phenotype, indicating that malfunctioning Rab7-directed autophagosome transport is involved in the disturbed, cytoplasmatic HCN4 accumulation in CVB3-expressing human pacemaker-like cells. Summarizing, the enterovirus CVB3 inhibits human cardiac pacemaker function by reducing the pacemaker channel plasma membrane density, an effect that can be corrected by pharmacological intervention of endocytic vesicle trafficking.