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. 2010 Dec 17;486(3):235-9.
doi: 10.1016/j.neulet.2010.09.061. Epub 2010 Sep 29.

Mitochondrial α-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo

Shankar J Chinta  1 , Jyothi K Mallajosyula, Anand Rane, Julie K Andersen
Affiliations

Mitochondrial α-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo

Shankar J Chinta et al. Neurosci Lett. .

Abstract

Alpha-synuclein is the major protein component of Lewy bodies, a cardinal pathological feature of the degenerating Parkinsonian brain. Alpha-synuclein has been reported to be able to intercalate into membranes via formation of an alpha-helical structure at its N-terminal end. Recent in vitro studies from various laboratories have demonstrated that α-synuclein can physically associate with mitochondria and interfere with mitochondrial function. α-Syn predominantly associates with the inner mitochondrial membrane, where it can apparently interact with complex I resulting in reduced mitochondrial complex I activity and increased free radical production. However, the effect of in vivo α-synuclein accumulation within dopaminergic neurons on mitochondrial function has not been thoroughly studied. Examination of transgenic animals which overexpress the familial mutant A53T form of the protein selectively within dopaminergic neurons reveals that A53T localizes to the mitochondrial membranes as monomers and oligomers particularly under conditions of proteasomal inhibitory stress, and that this localization coincides with a selective age-related mitochondrial complex I inhibition and decreased substrate-specific respiration along with increases in mitochondrial autophagy (mitophagy).

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Conflict of interest statement

Conflict of interest

The authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Expression of A53T α-syn in vivo results in its localization to the mitochondria in the form of monomers and oligomers. A, dual immunoytochemistry of TH-positive SN neuron using antibodies against synuclein (red) and outer mitochondrial membrane protein (VDAC, green). yellow = merged. B, Dual immunoytochemistry of TH-positive SN neuron using antibodies against synuclein (red) and inner mitochondrial membrane protein, complex V (ATPase, green). yellow= overlay. C. Anti-synuclein western blots of mitochondrial membrane fractions (75 μg each) isolated from the ST of 12 month old A53T (1) and A53T + epoxomicin (2) treated transgenics (M = molecular weight markers). *indicates monomer and red arrows indicate oligomers +/− proteasomal inhibition. Enrichment of the mitochondrial fractions was verified via western immunoblotting with the mitochondrial inner membrane protein ATPase and the cytoplasmic marker actin.
Fig. 2
Fig. 2
Quantitation of autophagic mitochondria in midbrain dopaminergic neurons of A53T high versus low-expressing α-syn-expressing transgenic mice (HE vs LE) at 12 months of age. A, Representative electron micrographs prepared from SN sections from pTH-A53T synuclein HE vs LE-expressing transgenics at 12 months of age. B, autophagic mitochondria versus total mitochondria were counted in at least three separate EM fields of midbrain dopaminergic neurons. n = 3; *p, 0.05 vs Low expressing transgenic (LE).
See this image and copyright information in PMC

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