Abstract
SummaryMitochondrial morphological and ultrastructural changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Here we investigate the role of the optic atrophy 1 (OPA1)-dependent cristae remodeling pathway in vivo and provide evidence that it regulates the response of multiple tissues to apoptotic, necrotic, and atrophic stimuli. Genetic inhibition of the cristae remodeling pathway in vivo does not affect development, but protects mice from denervation-induced muscular atrophy, ischemic heart and brain damage, as well as hepatocellular apoptosis. Mechanistically, OPA1-dependent mitochondrial cristae stabilization increases mitochondrial respiratory efficiency and blunts mitochondrial dysfunction, cytochrome c release, and reactive oxygen species production. Our results indicate that the OPA1-dependent cristae remodeling pathway is a fundamental, targetable determinant of tissue damage in vivo.
Highlights
Mitochondria are crucial organelles in energy conversion (Danial et al, 2003; Rizzuto et al, 2000), and, not surprisingly, impaired mitochondrial function affects organs where energy demand is high, like heart, skeletal muscle, and brain (DiMauro and Schon, 2003)
Mitochondrial morphological and ultrastructural changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear
We investigate the role of the optic atrophy 1 (OPA1)-dependent cristae remodeling pathway in vivo and provide evidence that it regulates the response of multiple tissues to apoptotic, necrotic, and atrophic stimuli
Summary
Highlights d Mice with controlled Opa overexpression are viable and grow normally d Opa protects from muscular atrophy, heart and brain ischemia, and liver apoptosis d Opa reduces ROS production and cytochrome c release d Opa1-controlled cristae remodeling is a targetable component of tissue damage. Varanita et al show that a mouse model of controlled overexpression of the master mitochondrial cristae biogenetic factor Opa resists skeletal muscle atrophy, heart and brain ischemic damage, and massive liver apoptosis by blunting mitochondrial dysfunction and cytochrome c release. Together with the accompanying paper by Civiletto et al, the authors offer a proof of principle of the potential for therapies targeting cristae remodeling in sporadic and genetic diseases.
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