Crosstalk between mitochondria–ER contact sites and the apoptotic machinery as a novel health meter

Mitochondria–endoplasmic reticulum (ER) contact sites (MERCS) are signaling hubs that are involved in vital cellular processes such as calcium signaling, lipid metabolism, autophagy, and apoptosis.Alterations in MERCS dynamics and composition are closely associated with severe human diseases such as neurodegenerative disorders and cancer.The BCL-2 protein family are primary regulators of mitochondrial apoptosis and key players in maintaining cellular homeostasis that operate at MERCS to fulfill essential cellular functions.Apoptotic machinery-induced cyclic GMP-AMP synthase (cGAS)–STING pathway activation and proinflammatory signaling require mitochondria–ER communication and are affected in cancer, Alzheimer's disease, and Parkinson's disease. Mitochondria–endoplasmic reticulum (ER) contact sites (MERCS) function as transient signaling platforms that regulate essential cellular functions. MERCS are enriched in specific proteins and lipids that connect mitochondria and the ER together and modulate their activities. Dysregulation of MERCS is associated with several human pathologies including Alzheimer's disease (AD), Parkinson's disease (PD), and cancer. BCL-2 family proteins can locate at MERCS and control essential cellular functions such as calcium signaling and autophagy in addition to their role in mitochondrial apoptosis. Moreover, the BCL-2-mediated apoptotic machinery was recently found to trigger cGAS–STING pathway activation and a proinflammatory response, a recognized hallmark of these diseases that requires mitochondria–ER interplay. This review underscores the pivotal role of MERCS in regulating essential cellular functions, focusing on their crosstalk with BCL-2 family proteins, and discusses how their dysregulation is linked to disease. Mitochondria–endoplasmic reticulum (ER) contact sites (MERCS) function as transient signaling platforms that regulate essential cellular functions. MERCS are enriched in specific proteins and lipids that connect mitochondria and the ER together and modulate their activities. Dysregulation of MERCS is associated with several human pathologies including Alzheimer's disease (AD), Parkinson's disease (PD), and cancer. BCL-2 family proteins can locate at MERCS and control essential cellular functions such as calcium signaling and autophagy in addition to their role in mitochondrial apoptosis. Moreover, the BCL-2-mediated apoptotic machinery was recently found to trigger cGAS–STING pathway activation and a proinfla