Browsing by Author "Busch, Karin B."

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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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    Inner mitochondrial membrane ultrastructure adaptations in the aging heart
    (ELSEVIER, 2022) Molina-Riquelme, Isidora; Gomez, Wileidy; Barrientos, Gonzalo; Diaz-Castro, Francisco; del Campo-Sefir, Andrea; Garrido, Luis; Morris, Silke; Breitsprecher, Leonhard; Psathaki, Katherina; Verdejo, Hugo; Busch, Karin B.; Eisner, Veronica
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    Mitochondrial cristae ultrastructure adaptations in the senescent heart
    (CELL PRESS, 2022) Barrientos, Gonzalo; Molina, Isidora E.; Gomez, Wileidy; Diaz-Castro, Francisco; delCampo-Sefir, Andrea; Garrido, Luis; Morris, Silke; Psathaki, Katherina; Verdejo, Hugo; Busch, Karin B.; Eisner, Veronica
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    Multi-scale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts
    (2025) Molina Riquelme, Isidora Elvira; Barrientos Guajardo, Gonzalo Andres; Breitsprecher, Leonhard; Gomez Calderon, Wileidy Andrea; Diaz Castro, Francisco Leopoldo; Morris, Silke; Campo Sfeir, Andrea del; Garrido Olivares, Luis Eugenio; Verdejo Pinochet, Hugo; Psathaki, Olympia Ekaterini; Busch, Karin B.; Eisner Sagüés, Verónica Raquel
    Aging is closely associated with cardiovascular diseases, the leading cause of mortality worldwide.Mitochondrial dysfunction is a hallmark of cardiovascular aging because it generates most of the heart's ATP at the cristae, specialized sub-compartments where OXPHOS takes place. In this study, we used multiple-scale electron microscopy approaches to evaluate age-related mitochondrial and cristaeultrastructural alterations in human and mouse hearts. We found that aged patients’ hearts displayed reduced cristae density as seen by TEM, even before any significant decline in the expression of cristae-shaping proteins. Similarly, a multi-scale approach that included SBF-SEM and TEM showed that in aged mice’s hearts cristae undergo ultrastructural remodeling processes, resulting in a decrease in cristae density and width. Electron tomography suggests an apparent decline in cristae connectivity, and an increase in fenestration size. These changes were linked to Opa1 downregulation, accompanied by reduced OXPHOS maximal respiration, but unrelated to alterations in the levels of OXPHOS core subunits and ATP synthase assembly. Altogether, this indicates that alterations in cristae structure alone are sufficient to impair oxidative metabolism, which highlights its potential as an early signal of cardiac aging, even before noticeable changes in mitochondrial morphology occur.