Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking alpha-synuclein.
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.
Ellis
Christopher E
CE
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Dr., MSC 4472, Bethesda, Maryland 20892-4472, USA.
Murphy
Eric J
EJ
Mitchell
Drake C
DC
Golovko
Mikhail Y
MY
Scaglia
Fernando
F
Barceló-Coblijn
Gwendolyn C
GC
Nussbaum
Robert L
RL
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004161:Diphenylhexatriene / Q000737:chemistry; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D004591:Electrophoresis, Polyacrylamide Gel; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D019308:Palmitic Acid / Q000378:metabolism; D010300:Parkinson Disease / Q000473:pathology; D010715:Phosphatidylglycerols / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013050:Spectrometry, Fluorescence; D013997:Time Factors; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D002308:Cardiolipins; D005227:Fatty Acids; D008055:Lipids; D010715:Phosphatidylglycerols; D010743:Phospholipids; D051844:alpha-Synuclein; D004161:Diphenylhexatriene; D016718:Arachidonic Acid; D019308:Palmitic Acid