Fig. 2

Mitochondrial dysfunction is a critical hallmark of neuronal failure present in AD, PD, HD, and ALS. Neuronal dysfunction is considered to be an early and pathological event in NDs. Hippocampal neuronal dysfunction in AD (a), neuronal failure in substantia nigra in PD (b), neuronal dysfunction in basal ganglia and striatum in HD (c), and motor cortex damage in ALS (d). Evidence has strongly suggested that mitochondrial failure plays a crucial role in neuronal dysfunction observed in NDs. In AD, bioenergetic failure is observed, which includes ROS overproduction, reduced ATP production, mitochondrial depolarization, calcium handling defects, along with excessive mitochondrial fragmentation (e). In PD, mitochondrial dysfunction is characterized by mitophagy failure. Several reports indicate that loss of PINK1 and Parkin leads to neuronal dysfunction. Also, mitochondria show a reduction of mitochondrial complex I activity, decreased Δψm, and increased mitochondrial fragmentation (f). In HD (g) and ALS (h), mitochondrial bioenergetic dysfunction is also reported, along with mitochondria traffic failure in neurites, preventing the arrival of mitochondria to areas of high energy demand, therefore leading to synaptic failure