The brain‐specific protein, p42 IP4 (ADAP 1) is localized in mitochondria and involved in regulation of mitochondrial Ca 2+

In brain, p42 IP4 (centaurin‐ α 1; recently named ADAP 1, which signifies ADP ribosylation factor GTPase activating protein with dual PH domains 1, within the large family of Arf‐GTPase activating proteins) is mainly expressed in neurons. p42 IP4 operates as a dual receptor recognising two second messengers, the soluble inositol(1,3,4,5)tetrakisphosphate and the lipid phosphatidylinositol(3,4,5)trisphosphate. We show here for the first time that p42 IP4 is localized in mitochondria, isolated from rat brain and from cells transfected with p42 IP4 . In rat brain mitochondria we additionally found interaction of p42 IP4 with 2′, 3′‐cyclic nucleotide 3′‐phosphodiesterase and α‐tubulin by pull‐down binding assay and by immunoprecipitation. In mitochondria from Chinese hamster ovary cells, p42 IP4 is predominantly associated with the intermembrane space and the inner membrane. This localization of p42 IP4 indicates that p42 IP4 might have a still unknown mitochondrial function. We studied whether p42 IP4 is involved in Ca 2+ ‐induced permeability transition pore opening, which is important in mitochondrial events leading to programmed cell death. We used mouse neuroblastoma cells as a model for the functional studies of p42 IP4 in mitochondria. In mitochondria isolated from p42 IP4 ‐transfected mouse neuroblastoma cells, over‐expression of p42 IP4 significantly decreased Ca 2+ capacity and lag time for Ca 2+ retention. Thus, we suggest that p42 IP4 is involved in the regulation of Ca 2+ transport in mitochondria. We propose that p42 IP4 promotes Ca 2+ ‐induced permeability transition pore opening and thus destabilizes mitochondria.