Mitochondrial Import and Accumulation of α-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain

• Published in: The Journal of biological chemistry Vol. 283; no. 14; pp. 9089 - 9100
• Main Authors: Devi, Latha, Raghavendran, Vijayendran, Prabhu, Badanavalu M., Avadhani, Narayan G., Anandatheerthavarada, Hindupur K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.04.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Aged; Aged, 80 and over; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Amino Acid Substitution; Dopamine - metabolism; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; Female; Humans; Male; Membrane Transport, Structure, Function, and Biogenesis; Middle Aged; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial Membranes - metabolism; Mitochondrial Membranes - ultrastructure; Mutation, Missense; Neurons - metabolism; Neurons - pathology; Organ Specificity - genetics; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Protein Sorting Signals - genetics; Protein Transport - genetics; Reactive Oxygen Species - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M710012200

α-Synuclein, a protein implicated in the pathogenesis of Parkinson disease (PD), is thought to affect mitochondrial functions, although the mechanisms of its action remain unclear. In this study we show that the N-terminal 32 amino acids of human α-synuclein contain cryptic mitochondrial targeting signal, which is important for mitochondrial targeting of α-synuclein. Mitochondrial imported α-synuclein is predominantly associated with the inner membrane. Accumulation of wild-type α-synuclein in the mitochondria of human dopaminergic neurons caused reduced mitochondrial complex I activity and increased production of reactive oxygen species. However, these defects occurred at an early time point in dopaminergic neurons expressing familial α-synuclein with A53T mutation as compared with wild-type α-synuclein. Importantly, α-synuclein that lacks mitochondrial targeting signal failed to target to the mitochondria and showed no detectable effect on complex I function. The PD relevance of these results was investigated using mitochondria of substantia nigra, striatum, and cerebellum of postmortem late-onset PD and normal human brains. Results showed the constitutive presence of ∼14-kDa α-synuclein in the mitochondria of all three brain regions of normal subjects. Mitochondria of PD-vulnerable substantia nigra and striatum but not cerebellum from PD subjects showed significant accumulation of α-synuclein and decreased complex I activity. Analysis of mitochondria from PD brain and α-synuclein expressing dopaminergic neuronal cultures using blue native gel electrophoresis and immunocapture technique showed the association of α-synuclein with complex I. These results provide evidence that mitochondrial accumulated α-synuclein may interact with complex I and interfere with its functions.