The work presented herein illustrates the multifaceted role of mitochondria inneurodegeneration and provides evidence supporting the use of mitochondria-targeted therapeutics in diseases involving oxidative stress and metabolic failure, namely Alzheimers disease (AD). The results implicate mitochondria-derived reactive species (RS) as a central mediator of neuronal apoptosis. The data suggest that while JNK activation is involved in many forms of apoptosis, it is not necessary for mitochondrial RS generation, which may explain its limited role in dictating apoptogenic cytochrome c redistrubution in trophic factor-deprived, sympathetic neurons isolated from mice. In order to provide a greater understanding of the relationship between mitochondrial oxidative stress and neuronal demise, mitochondria-targeted antioxidants were tested on in vitro models of neurodegeneration. MitoQ effectively attenuated all critical, mitochondria-dependent events associated with neuronal apoptosis, including superoxide production from the mitochondrial electron transport chain, cytochrome c redistribution, caspase activation, loss of mitochondrial membrane potential, and the ultimate death of the cell. MitoQ also prolonged the commitment to caspase-independent death by protecting the inner mitochondrial membrane (IMM). Conversely, MitoE2 had no effect on caspase-dependent and caspase-independent events leading to neuronal death, which may be due to inadequate accumulation within the IMM and the inability to sufficiently suppress mitochondrial RS. To determine whether the apparent mitochondrial protection conferred by MitoQ was sufficient to prevent the emergence of AD-associated neuropathology in vivo, young, triple-transgenic AD mice were treated with MitoQ for 5 months and the effect on AD progression was analyzed. The results indicate that MitoQ prevented the onset of cognitive decline, oxidative stress, A-accumulation, and activation of apoptotic machinery in female 3xTg-AD mice. These findings provide solid evidence of a role for mitochondrial RS in age dependent neurodegeneration and suggest mitochondria-targeted therapies hold great promise for the treatment of Alzheimers disease.
