Bone morphogenetic protein receptor 2 signaling mediates mitochondrial Ca2+ transport through its regulation of TAK1 splice variant

Résumé fourni par la source

Bone morphogenetic proteins (BMPs) are highly conserved multifunctional signaling proteins with pleotropic effects throughout embryonic development. BMPs are aberrantly expressed in many diseases including cancer and Alzheimer’s disease. Recent studies suggested that BMP signaling negatively regulates mitochondrial bioenergetics. The mechanisms by which BMP signaling regulates bioenergetics and cell survival are not known. We utilized BMP type 2 receptor (BMPR2) inhibitor (JL189), BMPR2 kinase domain KO, BMPR2 siRNA, and BMP loss of function mutants in C. elegans to inhibit BMP signaling (BMPR2i). The effects of BMPR2i on mitochondrial bioenergetics were examined by measuring differences in TCA cycle intermediates (mass spectrometer), mitochondrial respiration (Agilent Seahorse), and mitochondrial mass (MitoTracker Green/TFAM). Fluorescent mitochondrial Ca 2+ sensors Rhod-2AM and LAR-GECO were used to detect changes in mitochondrial Ca 2+ levels in cell culture and C elegans respectively. The KO and siRNA of the mitochondria uniporter (MCU) were used to determine the mechanisms BMPR2i regulates the uptake of Ca 2+ into the mitochondria. We compared the responses of BMPR2i in non-small cell lung cancer (NSCLC) cell lines, leukemia cells, breast cancer cells, and HT-22 mouse hippocampal cells to assess whether the biological response varied depending on the cell type. BMPR2i increased mitochondrial Ca 2+ (mtCa 2+ ) levels in all cells lines and in C. elegans , suggesting its regulation of Ca 2+ transport is conserved. BMPR2i induced increase in mtCa 2+ levels were dependent on the MCU, which effected mitochondrial bioenergetics and cell survival. In addition, our data suggests that BMPR2 regulation of mtCa 2+ transport is mediated by TAK1-d splice variant. In leukemia cells, BMPR2i induced significant cell death that was attenuated by MCU KO. In NSCLC and HT-22 cells, BMPR2i increased mitochondrial bioenergetics and induced minimal cell death. These studies reveal that BMPR2 signaling regulates TAK1-d splice variant to mediate mitochondrial Ca 2+ transport, which is dependent on the MCU. Our studies suggest that BMPR2 signaling utilizes mtCa 2+ transport to regulate both mitochondrial bioenergetics and/or cell survival. Our studies provide novel insight into how aberrant BMPR2 signaling is pathogenic and suggests that the response could vary depending on the cell type.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.