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Molecular and Cellular Biology, November 2005, p. 10190-10201, Vol. 25, No. 22
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.22.10190-10201.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mitochondrial Lipid Abnormality and Electron Transport Chain Impairment in Mice Lacking {alpha}-Synuclein{dagger}

Christopher E. Ellis,1 Eric J. Murphy,2 Drake C. Mitchell,3 Mikhail Y. Golovko,2 Fernando Scaglia,4 Gwendolyn C. Barceló-Coblijn,2 and Robert L. Nussbaum1*

Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892,1 Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58202-9037,2 Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892,3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 770304

Received 28 June 2005/ Returned for modification 13 August 2005/ Accepted 23 August 2005

The presynaptic protein {alpha}-synuclein, implicated in Parkinson disease (PD), binds phospholipids and has a role in brain fatty acid (FA) metabolism. In mice lacking {alpha}-synuclein (Snca–/–), total brain steady-state mass of the mitochondria-specific phospholipid, cardiolipin, is reduced 22% and its acyl side chains show a 51% increase in saturated FAs and a 25% reduction in essential n-6, but not n-3, polyunsaturated FAs. Additionally, 23% reduction in phosphatidylglycerol content, the immediate biosynthetic precursor of cardiolipin, was observed without alterations in the content of other brain phospholipids. Consistent with these changes, more ordered lipid head group and acyl chain packing with enhanced rotational motion of diphenylhexatriene (DPH) about its long axis were demonstrated in time-resolved DPH fluorescence lifetime experiments. These abnormalities in mitochondrial membrane properties were associated with a 15% reduction in linked complex I/III activity of the electron transport chain, without reductions in mitochondrial number, complex II/III activity, or individual complex I, II, III, or IV activity. Reduced complex I activity is thought to be a critical factor in the development of PD. Thus, altered membrane composition and structure and impaired complex I/III function in Snca–/– brain suggest a relationship between {alpha}-synuclein's role in brain lipid metabolism, mitochondrial function, and PD.

* Corresponding author. Mailing address: Genetic Disease Research Branch, National Human Genome Research Institute, NIH, 49 Convent Dr., MSC 4472, Bethesda, MD 20892-4472. Phone: (301) 402-2039. Fax: (301) 402-2170. E-mail: rlnuss{at}nhgri.nih.gov.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2005, p. 10190-10201, Vol. 25, No. 22
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.22.10190-10201.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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