Bioenergetic homeostasis is a vital process maintaining cellular health and has primary importance in neuronal cells due to their high energy demand markedly at synapses. Mitochondria, the metabolic hubs of the cells, are the organelles responsible for producing energy in the form of ATP by using nutrients and oxygen. Defects in mitochondrial homeostasis result in energy deprivation and can lead to disrupted neuronal functions. Mitochondrial defects adversely contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). Mitochondrial defects not only include reduced ATP levels but also increased reactive oxygen species (ROS) leading to cellular damage. Here, we detail the mechanisms that lead to neuronal pathologies involving mitochondrial defects. Furthermore, we discuss how to target these mitochondrial defects in order to have beneficial effects as novel and complementary therapeutic avenues in neurodegenerative diseases. The critical evaluation of these strategies and their potential outcome can pave the way for finding novel therapies for neurodegenerative pathologies.