Genetic ablation of calcium-independent phospholipase A2{gamma} leads to alterations in hippocampal cardiolipin content and molecular species distribution, mitochondrial degeneration, autophagy, and cognitive dysfunction.
Genetic ablation of calcium-independent phospholipase A(2)gamma (iPLA(2)gamma) results in profound alterations in hippocampal phospholipid metabolism and mitochondrial phospholipid homeostasis resulting in enlarged and degenerating mitochondria leading to autophagy and cognitive dysfunction. Shotgun lipidomics demonstrated multiple alterations in hippocampal lipid metabolism in iPLA(2)gamma(-/-) mice including: 1) a markedly elevated hippocampal cardiolipin content with an altered molecular species composition characterized by a shift to shorter chain length molecular species; 2) alterations in both choline and ethanolamine glycerophospholipids, including a decreased plasmenylethanolamine content; 3) increased oxidized phosphatidylethanolamine molecular species; and 4) an increased content of ceramides. Electron microscopic examination demonstrated the presence of enlarged heteromorphic lamellar structures undergoing degeneration accompanied by the presence of ubiquitin positive spheroid inclusion bodies. Purification of these enlarged heteromorphic lamellar structures by buoyant density centrifugation and subsequent SDS-PAGE and proteomics identified them as degenerating mitochondria. Collectively, these results identify the obligatory role of iPLA(2)gamma in neuronal mitochondrial lipid metabolism and membrane structure demonstrating that iPLA(2)gamma loss of function results in a mitochondrial neurodegenerative disorder characterized by degenerating mitochondria, autophagy, and cognitive dysfunction.
Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
David J
DJ
Mancuso
Paul
P
Kotzbauer
David F
DF
Wozniak
Harold F
HF
Sims
Christopher M
CM
Jenkins
Shaoping
S
Guan
Xianlin
X
Han
Kui
K
Yang
Gang
G
Sun
Ibrahim
I
Malik
Sara
S
Conyers
Karen G
KG
Green
Robert E
RE
Schmidt
Richard W
RW
Gross
D000818:Animals; D001343:Autophagy; D002308:Cardiolipins / Q000235:genetics / Q000378:metabolism*; D003072:Cognition Disorders / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006624:Hippocampus / Q000201:enzymology* / Q000648:ultrastructure; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000201:enzymology / Q000648:ultrastructure; D054512:Phospholipases A2, Calcium-Independent / Q000235:genetics / Q000378:metabolism*
D002308:Cardiolipins; D054512:Phospholipases A2, Calcium-Independent