Multiscale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts
Abstract
Aging is closely associated with cardiovascular diseases, the leading cause of mortality worldwide. Mitochondrial dysfunction is a hallmark of cardiovascular aging. Most of the heart’s ATP is produced at the cristae, specialized subcompartments where oxidative phosphorylation (OXPHOS) takes place. In this study, we used multiple-scale electron microscopy approaches to evaluate age-related mitochondrial and ultrastructural alterations of cristae in human and mouse hearts. We found that aged patients’ hearts displayed reduced cristae density as seen by transmission electron microscopy (TEM), even before any significant decline in the expression of cristae-shaping proteins. Similarly, a multiscale approach that included TEM and serial block-face scanning electron microscopy (SBF-SEM) 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 maximal OXPHOS respiration, but unrelated to alterations in the abundance 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (13)
Isidora Molina-Riquelme
Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile
Gonzalo Barrientos
Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile
Leonhard Breitsprecher
Center of Cellular Nanoanalytics, Integrated Bioimaging Facility, University of Osnabrück
Wileidy Gómez
Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile
Francisco Díaz-Castro
Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile
Silke Morris
Institute of Integrative Cell Biology and Physiology, Faculty of Biology, University of Muenster
Gonzalo Almarza
Laboratorio de Fisiología y Bioenergética Celular, Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile
Andrea del Campo
Laboratorio de Fisiología y Bioenergética Celular, Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile
Luis Garrido-Olivares
Laboratorio de Fisiología y Bioenergética Celular, Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile
Hugo E. Verdejo
Facultad de Medicina, División de Cirugía, Pontificia Universidad Católica de Chile
Olympia Ekaterini Psathaki
Center of Cellular Nanoanalytics, Integrated Bioimaging Facility, University of Osnabrück
Karin B. Busch
Institute of Integrative Cell Biology and Physiology, Faculty of Biology, University of Muenster
Verónica Eisner
Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile