Mitochondria are key players in the maintenance of cellular homeostasis, as they generate ATP via OXPHOS. As such, disruption in mitochondrial homeostasis is closely associated with disease states, caused by subtle alterations in the function of tissues or by major defects, particularly evident in tissues with high metabolic demands. Adaptations in mitochondrial copy number or mitochondrial mass, and the induction of genes implicated in OXPHOS or in intermediary metabolism as well, depend on the balanced contribution of both the nuclear and mitochondrial genomes. This forms a biogenesis program, controlled by several nuclear factors that act coordinately and in a categorized manner. Dynamic changes in mitochondrial regulators are associated with post-translational modifications mediated by metabolic sensors, such as SIRT1 and AMPK. Nrf2, which induces an antioxidant protective response against oxidative stress, also modulates bioenergetic function and metabolism. Additionally, the stability of mitochondrial transcripts is decreased by miRNA detected in the mitochondria, thus affecting the bioenergetic capacity of the cell. However, mitochondrial adaptation to metabolic demands is also dependent on the removal of damaged mitochondria (mitophagy) and fission/fusion events of the mitochondrial network.