Mitochondrial association of alpha-synuclein causes oxidative stress

Abstract

Alpha-synuclein is a neuron-specific protein that contributes to the pathology of Parkinson's disease via mitochondria-related mechanisms. The present study investigated possible interaction of alpha-synuclein with mitochondria and consequences of such interaction. Using SHSY cells overexpressing alpha-synuclein A53T mutant or wild-type, as well as isolated rat brain mitochondria, the present study shows that alpha-synuclein localizes at the mitochondrial membrane. In both SHSY cells and isolated mitochondria, interaction of alpha-synuclein with mitochondria causes release of cytochrome c, increase of mitochondrial calcium and nitric oxide, and oxidative modification of mitochondrial components. These findings suggest a pivotal role for mitochondria in oxidative stress and apoptosis induced by alpha-synuclein.

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Furthermore, in both SHͲSY5Y neuroblastoma cells and isolated rat mitochondria, alphaͲsyn seems to induce mitochondrial release of cytochrome c, increased mitochondrial calcium and NO, and oxidative modification of mitochondrial components. These findings suggest a pivotal role for mitochondria in oxidative stress and apoptosis induced by alphaͲsyn [186]. In a model of aging yeast, functional mitochondria are required for alphaͲsyn toxicity [187].…”

Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction

“…Because Ru360 abolished this effect, we can conclude that the downstream effects of mitochondria-associated ␣Syn were dependent on the uptake of Ca 2ϩ into the mitochondrial matrix. Previous reports suggest that overexpressing ␣Syn in cells or animals leads to alterations in mitochondrial morphology or function in the absence of overt Ca 2ϩ stress (27,31,36,37,58,59,70,71). These results could be explained by one or more of the following possibilities.…”

“…Few studies have directly investigated the effect of different forms of ␣Syn on mitochondrial function. One reported that incubation of isolated mitochondria with aggregated ␣Syn can increase markers of oxidative stress, but the aggregation state (fibrillar or oligomeric) was not thoroughly characterized (36). No previous studies have tested the role of mitochondrial Ca 2ϩ stress or specific respiratory substrates in the ability of diverse ␣Syn species to induce mitochondrial dysfunction.…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Some studies suggested that α-synuclein can be localized at mitochondria where it inhibits complex I (Devi et al, 2008;Liu et al, 2009;Loeb et al, 2010;Chinta et al, 2010), leading to increased ROS production (Devi et al, 2008;Parihar et al, 2008). Other studies demonstrated increased ROS levels and alterations in the expression levels of complex I subunits due to α-synuclein treatment or over-expression (Pennington et al, 2010;Wang et al, 2010).…”