ORP10 Maintains Mitochondrial Energy Metabolism by Modulating BCR-Evoked Ca²⁺ Signaling in Diffuse Large B-Cell...

The oxidative phosphorylation diffuse large B-cell lymphoma (Oxphos DLBCL) subtype is characterized by increased oxidative phosphorylation, but the mechanism underlying energy metabolism in Oxphos DLBCL cells is not well understood. Here, we first confirmed that oxysterol-binding protein-related protein 10 (ORP10) was highly expressed in Oxphos DLBCL cells tested and that ORP10 knockdown clearly inhibited Oxphos DLBCL cell tested proliferation in vitro and in vivo, and increased cell death. After screening interacting proteins, we found that ORP10 directly interacted with inositol 1,4,5-trisphosphate (IP₃) receptor 1 (IP₃R1), and that ORP10 knockdown reduced cytosolic and mitochondrial parallel Ca²⁺ spike oscillations, the oxygen consumption rate (OCR), and intracellular ATP levels, but had no impact on lactic acid production. In addition, ORP10 knockdown enhanced autophagic cell death in Oxphos DLBCL cells tested. These data support a novel model in which ORP10 associates with IP₃R1 and is required for robust IP₃R1-dependent Ca²⁺ responses, which maintain mitochondrial energetics in Oxphos DLBCL cells tested. Thus, ORP10 may represent a promising metabolic vulnerability marker of Oxphos DLBCL cells tested.