Mitochondria are cytoplasmic organelles in eukaryotic cells, crossroad of many metabolic pathways. Hypotheses on their origin include either a serial endosymbiotic event [1], or an autogenous model of eukaryotic origins, which predicts that the nucleus evolved before the acquisition of mitochondria [2], or a genomic chimera, in which a prokaryotic (archaebacterial) host cell acquired a eubacterial endosymbiont [3]. The ultimate result is the eukaryotic cell carrying two genomes, the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA), the latter hosting a multitude of genes transferred from the ancestral mtDNA during about two billions years of evolution [4, 5]. In a restrictive view, the main function of mitochondria is centred on the process of oxidative phosphorylation (OXPHOS), which provides the ATP supply to drive cellular functions [6]. OXPHOS presents the unique feature, amongst all other biochemical pathways of eukaryotic cells, of being controlled by both genomes, mtDNA and nDNA, forced to a tight, coordinated dialog, and forced to support each others’ existence in a mutual integration with huge implications for the development of multicellular life on the planet [7]. Initially downplayed as an irrelevant, small piece of DNA, mtDNA was rapidly elevated to its real importance as soon as the first human pathologies were clearly linked to mutations affecting this circular multicopy genome, opening in the year 1988 [8, 9] the field of mitochondrial medicine [10]. The field, in 1995, propagated from mtDNA to the nDNA genes encoding mitochondrial proteins [11], and both genomes became populated in the last 30 years by an exponentially growing list of human diseases and genetic defects ultimately associated with mitochondrial dysfunction, involving both paediatric and adult patients