Effect of NGF on the Subcellular Localization of Group IIA Secretory Phospholipase A2 (GIIA) in PC12 Cells: Role in Neuritogenesis

Abstract

Phospholipases A(2) (PLA(2)s) are involved in neuritogenesis but the identity of the isoforms(s) contributing to this process is still not defined. Several reports have focused on secretory PLA(2)s (sPLA(2)) as the administration of exogenous sPLA(2)s to PC12 neuronal cells stimulates neurite outgrowth. The present study demonstrates that the endogenous group IIA sPLA(2) (GIIA), constitutively expressed in mammalian neural cells, changes its subcellular localization when PC12 cells are induced to differentiate by NGF treatment. Indeed, confocal analysis showed a time-dependent accumulation of GIIA in growth cones and neurite tips. Under identical conditions the subcellular distribution of another isoform (GV) was unaffected by NGF. Contrary to GX, another sPLA(2) isoform expressed by PC12 cells, the contribution of GIIA to neuritogenesis does not require its release in the extracellular medium.

The neurotoxic secreted phospholipase A2 from the Vipera a. ammodytes venom targets cytochrome c oxidase in neuronal mitochondria

“…The mitochondrion is one of the most exciting cellular compartments regarding the pathophysiology of sPLA 2 s. Endogenous GIIA sPLA 2 has been detected in the mitochondrion under normal physiological conditions, under which it is apparently harmless to this organelle 10 . Apart from its role in neuritogenesis 11 , it has been speculated that this enzyme is also important for the fitness of the mitochondrion, due to its ability to hydrolyse oxidized fatty acid chains arising from its phospholipids such as cardiolipin, for assisting remodelling of mitochondrial membranes during fusion and fission of the organelle and during mitophagy 12,43 . Activation of the phospholipase activity in mitochondria is, on the other hand, connected, importantly, with excitotoxicity, oxidative stress and with the mitochondrial dysfunction due to induction of the mitochondrial permeability transition 12 .…”

“…It is not surprising though that endogenous GIIA sPLA 2 , very similar in structure to Atx, has been discovered in mitochondria of mammalian cells 10 . Besides the confirmed involvement of this enzyme in neuritogenesis 11 , other very important pathophysiological functions of GIIA sPLA 2 associated with mitochondria have been suggested 12,13 . Its association with the aetiology of some neurodegenerative diseases, for example Alzheimer’s disease 14–17 , is of the greatest relevance.…”