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Mitochondrial Stress and Cellular Senescence
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Irene L. Tan, Michael C. Velarde
Mitochondria sequester calcium ions to regulate oxidative phosphorylation, to induce the mitochondrial permeability transition (MPT) related to apoptosis, and to maintain mitochondrial and cellular calcium homeostasis (Gunter et al. 2004). Increased Ca2+ uptake depolarizes the mitochondrial membrane, causing a temporary decline in ATP production (Nguyen and Jafri 2005). Increased calcium loading in mitochondria also elevates cytosolic NADH levels and reduces sirtuin activity (Marcu et al. 2014), which can cause premature cell cycle arrest (Bolinches-Amoros et al. 2014; Ziegler, Wiley, and Velarde 2015). Conversely, depletion of the calcium channels inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) and mitochondrial calcium uniporter (MCU) allows escape from OIS (Wiel et al. 2014). In response to stress, mitochondria can also release stored calcium ions into the cytosol and trigger a retrograde response signaling to the nucleus and activate specific nuclear transcription factors (Butow and Avadhani 2004). For example, high intracellular calcium concentration results in phosphorylation of cAMP-responsive element-binding protein (CREB), increasing p53 recruitment to promoters, elevating p21 expression, and inhibiting cell proliferation (Arnould et al. 2002).
Inositol 1,4,5-trisphosphate receptor type 2 is associated with the bone–vessel axis in chronic kidney disease–mineral bone disorder
Published in Renal Failure, 2023
Qiong Xiao, Yun Tang, Haojun Luo, Sipei Chen, Qiao Tang, Rong Chen, Lin Xiong, Jun Xiao, Daqing Hong, Li Wang, Guisen Li, Yi Li
Regarding the unknown mechanisms of CKD–MBD, the results of the RNA sequencing in the present study identified the ITPR2 gene, encoding inositol 1,4,5-trisphosphate receptor 2 protein (IP3R2). ITPR2 can regulate calcium fluxes from the endoplasmic reticulum to the mitochondria [42,43] and is crucial for intracellular calcium homeostasis [44]. It can be commonly expressed in osteoclast precursors to regulate intercellular crosstalk between osteoblasts and osteoclasts to stimulate osteoclast differentiation [45]. Furthermore, Li et al. reported that the inositol phosphate metabolism pathway was significantly enriched in the bone of an osteoporosis rat model, suggesting the importance of the inositol phosphate metabolism pathway in bone metabolism diseases [46]. In the current study, RNA sequencing revealed that ITPR2 levels were significantly reduced in the aortas of the CKD–MBD rats. As a secretory protein, the serum ITPR2 levels in the CKD–MBD rats showed a significantly decrease at 4 weeks and a slightly increasing trend without statistical difference at 16 weeks. These levels were significantly increased in the serum of patients undergoing maintenance hemodialysis. Indeed, there is a discrepancy in the serum levels of ITPR2 between the CKD–MBD rat model and patients undergoing maintenance hemodialysis. Although the remnant kidney model is widely used, there are still some differences in the disease status between rat models and humans. Owing to the complicated heredity and environmental factors of patients undergoing maintenance hemodialysis, there might be a discrepancy in the serum levels of ITPR2 between the CKD–MBD rat model and patients. We will further study the precise mechanisms of heredity and environmental factors in patients undergoing maintenance hemodialysis upon ITPR2 secretion. We also agree that the results were influenced by the observation time. It is possible that the patients undergoing maintenance hemodialysis were too advanced in their state, and therefore, upregulation and not downregulation of ITPR2 levels was observed. It is more likely that the observation period was not long enough to observe the upregulation of ITPR2 levels in the rat model. ITPR2 levels were similar in the sham group between 4 and 16 weeks, but showed an upward trend in the CKD group from 4 to 16 weeks. Correlation analysis involving patients undergoing hemodialysis with vascular calcification revealed that serum ITPR2 levels were negatively correlated with BUN levels and positively correlated with TRACP-5B levels. Although we did not distinguish between patients with CKD–MBD and those without CKD–MBD, which would require a further series of systematic evaluation methods, all patients in the calcification group in the correlation analysis have clearly developed CKD–MBD. These reports from Kuroda et al. and Zhang et al. [47,48] support our results that osteoclasts can be activated with an increase in serum ITPR2 levels, leading to the loss of bone mass involving bone disorders. These findings provide preliminary insights into the role of ITPR2 in the potential association between bone and vessels in CKD–MBD.