Phosphatidic Acid ( PA)-preferring Phospholipase A1 Regulates Mitochondrial Dynamics

Background: Phosphatidic acid (PA) is involved in membrane dynamics. Results: PA-preferring phospholipase A(1) (PA-PLA(1)) affects mitochondrial morphology in an activity-dependent manner. Gene disruption of PA-PLA(1) in mice causes sperm malformation due to mitochondrial organization defects. Conclusion: PA-PLA(1) regulates mitochondrial dynamics. Significance: We demonstrate an in vivo function of PA-PLA(1) and suggest a possible mechanism of PA regulation of the mitochondrial membrane. Recent studies have suggested that phosphatidic acid (PA), a cone-shaped phospholipid that can generate negative curvature of lipid membranes, participates in mitochondrial fusion. However, precise mechanisms underling the production and consumption of PA on the mitochondrial surface are not fully understood. Phosphatidic acid-preferring phospholipase A(1) (PA-PLA(1))/DDHD1 is the first identified intracellular phospholipase A(1) and preferentially hydrolyzes PA in vitro. Its cellular and physiological functions have not been elucidated. In this study, we show that PA-PLA(1) regulates mitochondrial dynamics. PA-PLA(1), when ectopically expressed in HeLa cells, induced mitochondrial fragmentation, whereas its depletion caused mitochondrial elongation. The effects of PA-PLA(1) on mitochondrial morphology appear to counteract those of MitoPLD, a mitochondrion-localized phospholipase D that produces PA from cardiolipin. Consistent with high levels of expression of PA-PLA(1) in testis, PA-PLA(1) knock-out mice have a defect in sperm formation. In PA-PLA(1)-deficient sperm, the mitochondrial structure is disorganized, and an abnormal gap structure exists between the middle and principal pieces. A flagellum is bent at that position, leading to a loss of motility. Our results suggest a possible mechanism of PA regulation of the mitochondrial membrane and demonstrate an in vivo function of PA-PLA(1) in the organization of mitochondria during spermiogenesis.