The intricate relationship between calcium (Ca) homeostasis and mitochondrial function is crucial for cellular metabolic adaptation in tumor cells. Ca-initiated signaling maintains mitochondrial respiratory capacity and ATP synthesis, influencing critical cellular processes in cancer development. Previous studies by our group have shown that the homocysteine-inducible ER Protein with Ubiquitin-Like Domain 1 (HERPUD1) regulates inositol 1,4,5-trisphosphate receptor (ITPR3) levels and intracellular Ca signals in tumor cells. This study explores the role of HERPUD1 in regulating mitochondrial function and tumor cell migration by controlling ITPR3-dependent Ca signals. We found HERPUD1 levels correlated with mitoch... More
The intricate relationship between calcium (Ca) homeostasis and mitochondrial function is crucial for cellular metabolic adaptation in tumor cells. Ca-initiated signaling maintains mitochondrial respiratory capacity and ATP synthesis, influencing critical cellular processes in cancer development. Previous studies by our group have shown that the homocysteine-inducible ER Protein with Ubiquitin-Like Domain 1 (HERPUD1) regulates inositol 1,4,5-trisphosphate receptor (ITPR3) levels and intracellular Ca signals in tumor cells. This study explores the role of HERPUD1 in regulating mitochondrial function and tumor cell migration by controlling ITPR3-dependent Ca signals. We found HERPUD1 levels correlated with mitochondrial function in tumor cells, with HERPUD1 deficiency leading to enhanced mitochondrial activity. HERPUD1 knockdown increased intracellular Ca release and mitochondrial Ca influx, which was prevented using the ITPR3 antagonist xestospongin C or the Ca chelator BAPTA-AM. Furthermore, HERPUD1 expression reduced tumor cell migration by controlling ITPR3-mediated Ca signals. HERPUD1-deficient cells exhibited increased migratory capacity, which was attenuated by treatment with xestospongin C or BAPTA-AM. Additionally, HERPUD1 deficiency led to reactive oxygen species-dependent activation of paxillin and FAK proteins, which are associated with enhanced cell migration. Our findings highlight the pivotal role of HERPUD1 in regulating mitochondrial function and cell migration by controlling intracellular Ca signals mediated by ITPR3. Understanding the interplay between HERPUD1 and mitochondrial Ca regulation provides insights into potential therapeutic targets for cancer treatment and other pathologies involving altered energy metabolism.
