Mitochondria are cellular organelles that play a major role in various cellular processes, encompassing energy production, metabolism, calcium homeostasis, as well as regulated cell death and innate immunity. Alterations in mitochondrial permeability through mitochondrial pores serve as efficient mechanisms not only to communicate mitochondrial stress to the cell but also as a key event in the integration of cellular responses. Eukaryotic cells, in this regard, have evolved diverse signaling networks that sense and respond to the release of mitochondrial components into the cytosol, playing a crucial role in controlling cell death and inflammatory pathways. The tight regulation of mitochondrial functions relies on their interaction with the endoplasmic reticulum (ER) at mitochondria-ER contact sites (MERCS). These contacts are not only crucial for normal mitochondrial functions but also hold significance in disease contexts. Dysregulation of MERCS is linked to neuropathologies such as Alzheimer’s and Parkinson’s. Exploring the modulation of mitochondria-ER communication alongside apoptotic signaling machinery reveals promising therapeutic opportunities for neurodegeneration.