2026-04-14T19:28:45Zhttps://uvadoc.uva.es/oai/request

oai:uvadoc.uva.es:10324/778002025-09-24T07:18:32Zcom_10324_1134com_10324_931com_10324_894col_10324_1213

Nichtová, Zuzana Fernandez-Sanz, Celia Fuente Pérez, Sergio De La Yuan, Yuexing Hurst, Stephen Lanvermann, Sebastian Tsai, Hui-Ying Weaver, David Baggett, Ariele Thompson, Christopher Bouchet-Marquis, Cedric Várnai, Péter Seifert, Erin L. Dorn, Gerald W. Sheu, Shey-Shing Csordás, György Fuente Pérez, Sergio De La 2023 Producción Científica Background: Cardiac contractile function requires high energy from mitochondria, and Ca2+ from the sarcoplasmic reticulum (SR). Via local Ca2+ transfer at close mitochondria-SR contacts, cardiac excitation feedforward regulates mitochondrial ATP production to match surges in demand (excitation-bioenergetics coupling). However, pathological stresses may cause mitochondrial Ca2+ overload, excessive reactive oxygen species production and permeability transition, risking homeostatic collapse and myocyte loss. Excitation-bioenergetics coupling involves mitochondria-SR tethers but the role of tethering in cardiac physiology/pathology is debated. Endogenous tether proteins are multifunctional; therefore, nonselective targets to scrutinize interorganelle linkage. Here, we assessed the physiological/pathological relevance of selective chronic enhancement of cardiac mitochondria-SR tethering. Methods: We introduced to mice a cardiac muscle-specific engineered tether (linker) transgene with a fluorescent protein core and deployed 2D/3D electron microscopy, biochemical approaches, fluorescence imaging, in vivo and ex vivo cardiac performance monitoring and stress challenges to characterize the linker phenotype. Results: Expressed in the mature cardiomyocytes, the linker expanded and tightened individual mitochondria-junctional SR contacts; but also evoked a marked remodeling with large dense mitochondrial clusters that excluded dyads. Yet, excitation-bioenergetics coupling remained well-preserved, likely due to more longitudinal mitochondria-dyad contacts and nanotunnelling between mitochondria exposed to junctional SR and those sealed away from junctional SR. Remarkably, the linker decreased female vulnerability to acute massive β-adrenergic stress. It also reduced myocyte death and mitochondrial calcium-overload-associated myocardial impairment in ex vivo ischemia/reperfusion injury. Conclusions: We propose that mitochondria-SR/endoplasmic reticulum contacts operate at a structural optimum. Although acute changes in tethering may cause dysfunction, upon chronic enhancement of contacts from early life, adaptive remodeling of the organelles shifts the system to a new, stable structural optimum. This remodeling balances the individually enhanced mitochondrion-junctional SR crosstalk and excitation-bioenergetics coupling, by increasing the connected mitochondrial pool and, presumably, Ca2+/reactive oxygen species capacity, which then improves the resilience to stresses associated with dysregulated hyperactive Ca2+ signaling. application/pdf https://uvadoc.uva.es/handle/10324/77800 eng Enhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle Remodeling info:eu-repo/semantics/article TEXT UVaDOC. Repositorio Documental de la Universidad de Valladolid Hispana