Fig. 4.

Mitochondrial dysfunctions and Ca²⁺ homeostasis in ALS and HD. Mutant SOD1 in ALS and mutant Htt in HD enhance intracellular Ca²⁺ permeability, impair mitochondrial membrane potential and increase the susceptibility to mitochondrial Ca²⁺ overload, thus inducing mPTP opening, the release of cytochrome c (cyt c) and apoptosis. Mutant Htt increases ER Ca²⁺ release by acting on the InsP₃R. Mutant VAPD (a protein found associated with mutant forms of ALS) enhances ER-mitochondria tethering, leading to an augmented mitochondrial Ca²⁺ uptake. Increased mitochondrial Ca²⁺ concentration, in turn, stimulates TCA cycle enzymes generating NADH and increasing ATP synthesis and ROS production.