Mitochondrial DNA: Defects, Maintenance Genes and Depletion

Mitochondria constitute a graticule dynamic cellular compartment present in the vast majority of eukaryotic cells. They produce most of the cellular energy by burning metabolic fuels. In addition, these organelles are involved in other essential processes such as nucleotide and iron-sulfur cluster biosynthesis, amino acid metabolism, fatty acid oxidation, calcium homeostasis, apoptosis, etc. Mitochondria contain their own genome, mtDNA, reminiscent of their bacterial origin. The mtDNA encodes 13 out of the 1500 estimated mitochondrial proteins and part of the machinery to translate them: 2 ribosomal RNAs (mt-rRNAs) and 22 tRNAs (mt-tRNAs). The remaining mitochondrial proteins are encoded in the nucleus, synthesized in the cytosol and imported into the mitochondria. The 13 mtDNA-encoded proteins are structural subunits of the energy producing system (the OXPHOS system), whose alterations provoke so-called mitochondrial OXPHOS diseases, a genetic and clinical heterogeneous group of disorders. The cellular mtDNA content, different according to the cell’s metabolic and energy requirements, is based on its replication machinery which is formed by a number of nuclear-encoded proteins, including DNA polymerase γ subunits PolG1 and PolG2, mtDNA helicase (Twinkle), single stranded binding protein (mtSSB), mtRNA polymerase (POLRMT/mtRNAP) and others. Functional alterations in any of these proteins or in those involved in the supply of deoxyribonucleotide triphosphate (dNTP) or in those controlling mitochondrial dynamics may provoke disorders characterized by the instability of the mtDNA, causing deletions and depletion. This chapter focuses on the molecular basis of these disorders.