Mitochondrial interaction of alpha-synuclein leads to irreversible translocation and complex I impairment.

MARTINEZ J; FUENTES, FEDERICO; VAGNASCO V; ALVAREZ S; ALAIMO A; CASSINA A; COLUCCIO LESKOW F.; VELAZQUEZ F

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2018

0003-9861

α-synuclein is involved in both familial and sporadic Parkinson´s disease. Although its interaction with mitochondria has been well documented several aspects remains unknown or under debate; such as the specific sub-mitochondrial localization of α-synuclein or the dynamics of the interaction. It has been suggested that α-synuclein could only interact with ER-associated mitochondria. Variety of model systems and experimental conditions makes difficult to compare results and extract definitive conclusions. Here we tackle these issues and analyze this interaction in a simplified model system consisting of purified α-synuclein and isolated rat brain mitochondria. This work shows that wild type α-synuclein interacts with isolated mitochondria without the need of any other cellular component and it is able to translocate into mitochondrial matrix. We present as well that this interaction and the irreversibility of the α-synuclein translocation depend on the time of incubation and α-synuclein concentration. FRET experiments show that α-synuclein localizes close to components of the TOM complex what it would be compatible with a passive transport of α-synuclein through the outer membrane. In addition, we describe how α-synuclein binding alters mitochondrial function at the level of Complex I what correlates with a decrease in ATP synthesis and an increase of ROS production.