Mitochondria and ER are closely connected through MAM (mitochondria associated membranes). ER stress leads to increased cytosolic calpain1 and 2 (csCPN1/2) activities that cleave beclin1 and Atg7 (autophagy protein 7). The decreased contents of beclin1 and Atg7 impair autophagosome formation that decreases mitophagy. ER stress-induced mitochondrial calcium overload activates mitochondrial calpain 1 and 2 (mCPN1/2) that leads to the degradation of metabolic enzymes and protein subunits of the respiratory complexes. The damaged individual complexes including complex I (CI), III (CIII), and IV (CIV) result in the disruption of supercomplexes. Calcium overload also triggers MPTP opening in aged heat mitochondria. (OMM, mitochondrial outer membrane; IMM, mitochondrial inner membrane; IMS, intermembrane space).