Abstract

ATAD3 protein is a S100B- and PKC-regulated mitochondrial ATPase which is vital for mitochondrial biogenesis and early development. Even if suspected today to contribute in a lipid rafts transfer system, from endoplasmic reticulum to mitochondria, the precise function of ATAD3 is still unknown. However, ATAD3 has been previously shown to exhibits in vitro anti-proliferative and chemo resistant properties and to be a positive marker of different tumor subtypes, of tumor progression and of poor survival in several human cancers. This is particularly true concerning ATAD3B, the embryonic and cancer-expressed isoform. Because ATAD3 is hypothetically implicated in lipid fluxes between endoplasmic reticulum and mitochondria, like S100B itself, we asked whether ATAD3B anti-proliferative and chemo resistant effects are dependent on available phospholipids from extra-cellular source. Using ATAD3B expressing and control cells, we show here that ATAD3B-related biological functions are dependent on the lipids in the medium. Complementation of lipid-free medium with individual lipids shows that phosphatidyl-serine and phosphatidyl-ethanolamine specifically enhance the growth of ATAD3B over expressing cells. Also, because S100B is a partner and regulator of ATAD3A/B, we investigated S100B localization following lipid starvation and exogenous phosphatidyl-serine delivery. We observed that endogenous S100B is first recruited to the plasma membrane and then to the mitochondria rapidly after phosphatidyl-serine addition. Finally, the in vivo mitochondrial localization of S100B was found in agreement with the in vitro interaction of S100B with mitochondria. These results reinforce the putative role of ATAD3 and S100B in Reticulum-Mitochondria interactions, like for the transport of phosphatidyl-serine between these compartments.

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