RT info:eu-repo/semantics/article
T1 Enhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle Remodeling
A1 Nichtová, Zuzana
A1 Fernandez-Sanz, Celia
A1 De La Fuente, Sergio
A1 Yuan, Yuexing
A1 Hurst, Stephen
A1 Lanvermann, Sebastian
A1 Tsai, Hui-Ying
A1 Weaver, David
A1 Baggett, Ariele
A1 Thompson, Christopher
A1 Bouchet-Marquis, Cedric
A1 Várnai, Péter
A1 Seifert, Erin L.
A1 Dorn, Gerald W.
A1 Sheu, Shey-Shing
A1 Csordás, György
A1 Fuente Pérez, Sergio De La
AB 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.
SN 0009-7330
YR 2023
FD 2023
LK https://uvadoc.uva.es/handle/10324/77800
UL https://uvadoc.uva.es/handle/10324/77800
LA eng
NO Nichtová Z, Fernandez-Sanz C, De La Fuente S, Yuan Y, Hurst S, Lanvermann S, Tsai HY, Weaver D, Baggett A, Thompson C, Bouchet-Marquis C, Várnai P, Seifert EL, Dorn GW 2nd, Sheu SS, Csordás G. Enhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle Remodeling. Circ Res. 2023 May 26;132(11):e171-e187. doi: 10.1161/CIRCRESAHA.122.321833. Epub 2023 Apr 14. PMID: 37057625; PMCID: PMC10213149.
NO Producción Científica
DS UVaDOC
RD 20-sep-2025