Sphingosine‐1‐phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration

Abstract

The potent lipid mediator sphingosine-1-phosphate (S1P) regulates diverse physiological processes by binding to 5 specific GPCRs, although it also has intracellular targets. Here, we demonstrate that S1P, produced in the mitochondria mainly by sphingosine kinase 2 (SphK2), binds with high affinity and specificity to prohibitin 2 (PHB2), a highly conserved protein that regulates mitochondrial assembly and function. In contrast, S1P did not bind to the closely related protein PHB1, which forms large, multimeric complexes with PHB2. In mitochondria from SphK2-null mice, a new aberrant band of cytochrome-c oxidase was detected by blue native PAGE, and interaction between subunit IV of cytochrome-c oxidase and PHB2 was greatly reduced. Moreover, depletion of SphK2 or PHB2 led to a dysfunction in mitochondrial respiration through cytochrome-c oxidase. Our data point to a new action of S1P in mitochondria and suggest that interaction of S1P with homomeric PHB2 is important for cytochrome-c oxidase assembly and mitochondrial respiration.

Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury

“…It remains to be determined whether the protective effect of S1P on mitochondria is mediated through intracellular cascades triggered by binding to its cell surface receptor (S1P1) or through a direct effect of S1P on mitochondria. 44,45 In summary, we have demonstrated that PT-S1P1 is an important target to attenuate cisplatin-induced AKI by preserving mitochondrial function and morphology. We conclude that targeting PT-S1P1 may represent a novel strategy in the prevention of cisplatin-induced AKI.…”

Sphingosine Kinase 1 Regulates Tumor Necrosis Factor-mediated RANTES Induction through p38 Mitogen-activated Protein Kinase but Independently of Nuclear Factor κB Activation

“…SK1 is primarily cytoplasmic and translocates to the plasma membrane upon activation (6), whereas SK2 can be found in the endoplasmic reticulum, nucleus, and mitochondria (7). The generation of S1P by SK1 can exert its signaling effects through two routes.…”

The role of sphingosine-1-phosphate in the tumor microenvironment and its clinical implications

“…[26][27][28][29] SphK2 in mitochondria produces S1P that interacts with prohibitin 2 to regulate complex IV assembly and respiration. 30 Furthermore, S1P produced by SphK1 can function as a cofactor for the E3 ubiquitin ligase activity of TRAF2 in nuclear factor-κB (NF-κB) signaling. 31 In sum, S1P produced by SphK2 or SphK1 can act inside the cell to regulate a variety of cellular functions, while S1P produced by SphK1 can act outside the cell to affect the TME through "inside-out" signaling.…”