Cyclophilin D: a therapeutic target to counteract reactive oxygen species-mediated damage in neurodegenerative disease?

Abstract

Age-related neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease represent a growing socio-economic burden in countries where average life expectancy is increasing (Lang, 2010). As such, gaining a better understanding of the multiple mechanisms underlying neurodegeneration is an essential first step towards the development of therapeutic approaches to disease prevention and intervention. Interestingly, despite the fact that most neurodegenerative disorders affect specific cell populations, there is strong evidence that many of these diseases share some common pathogenic hallmarks, including oxidative stress, mitochondrial dysfunction and neuronal cell death (Moreira et al. , 2010). Importantly, these features appear closely intertwined. This is perhaps best illustrated by the observations that mitochondrial dysfunction can lead to excessive production of reactive oxygen species and the activation of cell death pathways. Each of these processes may in turn be linked, either directly or indirectly, to depolarization of the inner mitochondrial membrane, dysfunction of the respiratory chain, ATP depletion and/or the opening of the mitochondrial permeability transition pore (mPTP) (Moreira et al. , 2010). This pore is a cyclophilin D (CypD)-regulated high conductance inner membrane channel that, upon prolonged opening, causes either apoptosis or necrosis (Di Lisa et al. , 2011). CypD is a mitochondrial matrix protein that initiates mPTP opening by binding to the inner mitochondrial membrane, a process that is regulated by Ca2+ overload, inorganic phosphate and oxidative stress (Di Lisa …