Axonal transport of membranous organelles such as mitochondria is essential for neuron viability and function. How signaling mechanisms regulate or influence mitochondrial distribution and transport is still largely unknown. We observed an increase in the distal distribution of mitochondria in neurons upon the expression of pleckstrin homology (PH) domains of phospholipase Cδ1 (PLCδ-PH) and spectrin (spectrin-PH). Quantitative analysis of mitochondrial transport showed that specific binding of PH domains to phosphatidylinositol (4,5) bisphosphate (PtdIns(4,5)P2) but not 3′ phosphorylated phosphatidylinositol species enhanced plus-end–directed transport of mitochondria two- to threefold and at the same time decreased minus-end–directed transport of mitochondria along axonal microtubules (MTs) without altering the overall level of motility. Further, the velocity and duration of mitochondrial transport plus the association of molecular motors with mitochondria remained unchanged by the expression of PH domains. Thus, PtdIns(4,5)P2-specific PH domains caused an increase in distal mitochondria by disturbing the balance of plus- and minus-end–directed transport rather than directly affecting the molecular machinery involved. Taken together our data reveal that level and directionality of transport are separable and that PtdIns(4,5)P2 has a novel role in regulation of the directionality of axonal transport of mitochondria
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