Figure 1.

Mitochondrial dysfunction in sporadic forms of ALS. Mitochondrial bioenergetics is driven by the oxidation of different substrates and is stimulated by calcium. Flux of electrons through the electron transport chain creates a transmembrane proton gradient of about 160 mV in the resting state (negative inside), which fuels ATP synthesis in the mitochondrial matrix. Leak of electrons in some of the bioenergetic reactions generates reactive oxygen species (ROS) that are involved in important cellular signaling processes but that, when in excess, may also lead to cellular dysfunction and death. Fibroblasts from sALS patients showed markers of mitochondrial dysfunction, compared to control fibroblasts, including decreased activity of metabolic dehydrogenases, increased ROS levels, increased intracellular calcium levels, decreased expression of components of the oxidative phosphorylation system, decreased mitochondrial potential, oxygen consumption, and ATP levels [68]. Abbreviations: NAD: β-Nicotinamide adenine dinucleotide; NADH: β-Nicotinamide adenine dinucleotide 2′-phosphate reduced form; FAD: Flavin Adenine Dinucleotide; CI: Complex I; CII: Complex II; CIII: Complex III; CIV: Complex IV; Cyt c: Cytochrome c; ETF: electron transfer flavoprotein; ROS: reactive oxygen species; DH: dehydrogenase; MCU: mitochondrial calcium uniporter; MPC: mitochondrial pyruvate carrier; ΔΨm: mitochondrial transmembrane electric potential; ATP: adenosine triphosphate; ADP: adenosine diphosphate; IMM: inner mitochondrial membrane