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Mitochondrial biogenesis is a complex process that depends on the coordinated expression of genes encoded in two different genomes, the nuclear and the mitochondrial genome. In response to extracellular signals and environmental cues and based on the communication between the mitochondria and nucleus, this process is strictly controlled during cell differentiation to supply different tissues with the correct number of functional mitochondria. To understand the physiopathology of mitochondrial biogenesis, it is critical to unravel the biochemical and molecular basis of this intergenomic cross‑talk. In mammals, cofactors of the PGC‑1 family are fundamental to integrate the response of specific transcription factors. In particular, Nuclear Respiratory Factors 1 and 2 activate the expression of a wide variety of respiratory genes. This regulatory transcriptional circuit is poorly documented in Drosophila, although a well conserved element, the Nuclear Respiratory Gene element, could play an important role in orchestrating energetic metabolism. In addition, the Drosophila DNA replication‑related element binding factor (DREF) regulates the expression of genes encoding critical elements of mtDNA metabolism, establishing a molecular link between mtDNA and nDNA replication. The use of Drosophila mutants with impaired oxidative phosphorylation has facilitated the study of several pathways involved in nuclear‑mitochondrial communication.