Abstract
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 A1 (PA-PLA1)/DDHD1 is the first identified intracellular phospholipase A1 and preferentially hydrolyzes PA in vitro. Its cellular and physiological functions have not been elucidated. In this study, we show that PA-PLA1 regulates mitochondrial dynamics. PA-PLA1, when ectopically expressed in HeLa cells, induced mitochondrial fragmentation, whereas its depletion caused mitochondrial elongation. The effects of PA-PLA1 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-PLA1 in testis, PA-PLA1 knock-out mice have a defect in sperm formation. In PA-PLA1-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-PLA1 in the organization of mitochondria during spermiogenesis.
Highlights
Phosphatidic acid (PA) is involved in membrane dynamics
PA-PLA1 Is Involved in Mitochondrial Dynamics—PA-PLA1 is predominantly expressed in mature testis and brain and at low levels in other tissues including HeLa cells (Ref. 12 and Fig. 1A)
To explore the function of PA-PLA1 in mitochondrial dynamics, PA-PLA1 with a FLAG tag was overexpressed in HeLa cells, and mitochondrial morphology was examined by immunofluorescence microscopy
Summary
Phosphatidic acid (PA) is involved in membrane dynamics. Results: PA-preferring phospholipase A1 (PA-PLA1) affects mitochondrial morphology in an activity-dependent manner. Significance: We demonstrate an in vivo function of PA-PLA1 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. Our results suggest a possible mechanism of PA regulation of the mitochondrial membrane and demonstrate an in vivo function of PA-PLA1 in the organization of mitochondria during spermiogenesis. Mitochondria are dynamic organelles, and their morphology is regulated by the balance between fusion and fission These processes are mediated by GTPases: fusion of the outer and inner membranes is mediated by Mitofusin (Mfn) and Opa, respectively, and fission is mediated by Drp1 [6]. Recent studies demonstrated that MitoPLD and Lipin 1 phosphatase reciprocally regulate the dynamics of mitochondria. Ablation of the PA-PLA1 gene caused defects in the organization of mitochondria during spermiogenesis, leading to sperm malformation and male subfertility
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