Figure 3.

Calcium overload and DNP. (A) The cytosolic Ca²⁺ under normal conditions is kept low and released from the mitochondria for signaling [1]. However, for conditions related to unfolded protein response (UPR) that lead to ER stress such as Huntington Disease [41,42] or mutations directly of ER function such as Wolfram Syndrome [43] or loss of dystrophin in the case of Duchenne Muscular Dystrophy [44], calcium levels rise in the cytosol and subsequently in the mitochondria. If the threshold for mitochondrial Ca²⁺ storage is exceeded, the mitochondrial permeability transition pore (mPTP) is formed and the mitochondria are destroyed setting up a cascade for neighboring mitochondrial destruction [16]. (B) Calcium overload of the mitochondria may be reduced, even in the presence of a sudden rise of cytosol Ca²⁺ from the ER, in TBI and other conditions of metabolic stress, in the presence of DNP by closing the calcium uniporter channel. Reduced intra-mitochondrial calcium removes the driving force toward apoptosis, thereby saving the neuron, myotube and other at-risk cell types.