Lakhasly

Advances in microscopy have revealed specific contact points between the ER and other organelles, forming regulated pathways for interorganelle communication crucial for cellular homeostasis. One well-studied example is the interaction between ER and mitochondria, forming mitochondria-associated ER membranes (MAMs). MAMs are involved in various cellular functions, including mitochondrial metabolism, lipid exchange, apoptosis, and Ca2+ and ROS signaling. The ER is a major intracellular calcium store, and calcium release from the ER can affect mitochondrial function. Ca2+ exchange between the ER and mitochondria is closely linked to redox signaling, and ER stress can influence signaling in MAMs, impacting cell fate. During ER stress, changes in MAMs lead to increased Ca2+ influx from the ER to mitochondria, triggering mitochondrial ROS generation and the opening of mPTPs, resulting in cell death. NOX4, enriched in MAMs, promotes pro-survival signaling in response to stress in cardiomyocytes by inhibiting ER-mitochondrial Ca2+ influx and mPTP-dependent necrosis. Redox regulation of MAMs plays a role in cardiac remodeling in response to hypertension and other cardiovascular diseases. MAM-related proteins accumulate in cardiomyocytes during the initial stage of cardiac hypertrophy. MAMs are also involved in inflammation of the rostral ventrolateral medulla (RVLM), contributing to sympathetic hyperactivity in stress-induced hypertension. Reduced expression of sigma-1R (s-1R), an ER chaperone enriched in MAMs, in the RVLM during stress-induced hypertension leads to decreased ER-mitochondria contact. Administration of SKF10047, an s-1R agonist, reduces mitochondrial ROS production and RVLM neuroinflammation, ameliorating sympathetic hyperactivity in hypertensive rats.

Advances in fluorescence and electron microscopy have uncovered specific physical contact points between the ER and other organelles such as the plasma membrane, endosomes, Golgi complex, and mitochondria. These regulated contact sites act as pathways for interorganelle communication, which is essential for maintaining cellular homeostasis.112 A well documented example is the interaction between ER and mitochondria, which leads to the formation of specific zones termed mitochondria-associated ER membranes (MAMs). MAMs play pivotal roles in diverse cellular functions, including mitochondrial metabolism, lipid exchange, apoptosis, Ca2þ, and ROS signalling.113 The ER is a major intracellular calcium store, and calcium release from the ER can affect mitochondrial function. Ca2þ exchange between the ER and mitochondria is intimately associated with redox signalling, and activation of ER stress can affect signalling in MAMs, influencing cell fate.114 During ER stress, changes in MAMs are associated with an increase in the influx of Ca2þ from ER to mitochondria, which is involved in increased mitochondrial ROS generation and triggers the opening of the mitochondrial permeability transition pores (mPTPs), resulting in cell death.115 NOX4 is enriched in MAMs and plays an important role in pro-survival signalling in response to stress in cardiomyocytes. NOX4 promotes phosphorylation of inositol trisphosphate receptors by Akt, resulting in inhibition of ER-mitochondrial Ca2þ influx and mPTP-dependent necrosis.116 Redox regulation of MAMs plays an important role in cardiac remodelling in response to hypertension and other cardiovascular diseases. Single-cell transcriptional profiling of hearts during transverse aortic constrictioneinduced cardiac hypertrophy in mice showed that MAM-related proteins preferentially accumulated in cardiomyocytes during the initial stage of cardiac hypertrophy.117 MAMs are also involved in inflammation of the rostral ventrolateral medulla (RVLM), which underlies sympathetic hyperactivity in stressinduced hypertension. Expression of sigma-1R (s-1R), an ER chaperone that is enriched in MAMs, is reduced in the RVLM of rats during stress-induced hypertension, leading to decreased ER-mitochondria contact. Administration of SKF10047, a s-1R agonist, reduced mitochondrial ROS production and RVLM neuroinflammation, subsequently ameliorating sympathetic hyperactivity in hypertensive rats