Caloric restriction protects livers from ischemia/reperfusion damage by preventing Ca2+-induced mitochondrial permeability transition

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Sergio L. Menezes-Filho, Ignacio Amigo, Fernanda M. Prado, Natalie C. Ferreira, Marcia K. Koike, Isabella F.D. Pinto, Sayuri Miyamoto, Edna F.S. Montero, Marisa H.G. Medeiros, Alicia J. Kowaltowski
Caloric restriction (CR) promotes lifespan extension and protects against many pathological conditions, including ischemia/reperfusion injury to the brain, heart and kidney. In the liver, ischemia/reperfusion damage is related to excessive mitochondrial Ca²⁺ accumulation, leading to the mitochondrial permeability transition. Indeed, liver mitochondria isolated from animals maintained on CR for 4 months were protected against permeability transition and capable of taking up Ca²⁺ at faster rates and in larger quantities. These changes were not related to modifications in mitochondrial respiratory activity, but rather to a higher proportion of ATP relative to ADP in CR liver mitochondria. Accordingly, both depletion of mitochondrial adenine nucleotides and loading mitochondria with exogenous ATP abolished the differences between CR and ad libitum (AL) fed groups. The prevention against permeability transition promoted by CR strongly protected against in vivo liver damage induced by ischemia/reperfusion. Overall, our results show that CR strongly protects the liver against ischemia/reperfusion and uncover a mechanism for this protection, through a yet undescribed diet-induced change in liver mitochondrial Ca²⁺ handling related to elevated intramitochondrial ATP.

Graphical abstract

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