Mitochondrial Lipid Abnormality and Electron Transport Chain Impairment in Mice Lacking α-Synuclein

Abstract

The presynaptic protein α-synuclein, implicated in Parkinson disease (PD), binds phospholipids and has a role in brain fatty acid (FA) metabolism. In mice lacking α-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 α-synuclein's role in brain lipid metabolism, mitochondrial function, and PD.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

We thank Bill Craigen for helping to support our studies, Douglass Turnbull for helpful advice, Anna Sirota for excellent technical assistance, and Douglas Wallace and Vincent Procaccio for helpful discussions and exploratory experiments.

This work was supported, in part, by the Intramural Research Program of the National Human Genome Research Institute, NIH, and NIH grants 1R21 NS043697-01A and 5P20R01-7699-02 to E.J.M.

We declare that we have no competing financial interests.