Two distinct genetic systems encode mitochondrial proteins: mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). mtDNA is a small 16.6 kb circle of double stranded DNA that codes for 13 respiratory chain polypeptides and 24 nucleic acids (two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs)) that are needed for intramitochondrial protein synthesis (fig 3).6 Nuclear genes code for the majority of mitochondrial respiratory chain polypeptides.13 These polypeptides are synthesised in the cytoplasm with a mitochondrial targeting sequence that directs them through the translocation machinery spanning the outer and inner membranes. The targeting sequence is then cleaved before the subunit is assembled with its counterparts on the inner mitochondrial membrane. The components of the import machinery ("TIM" and "TOM" proteins), the importation processing enzymes, and the respiratory chain assembly proteins are all the products of nuclear genes.
Nuclear genes are also important for maintaining the mitochondrial genome, including those encoding the mitochondrial DNA polymerase
(POLG1)
19 and products that maintain an appropriate balance of free nucleotides within the mitochondrion (TP, TK, DGK, and ANT1).
20–23 A recently described gene, C10orf2, codes for a helicase-like protein called Twinkle that appears to be important for mtDNA maintenance.
24 Nuclear DNA also codes for essential factors needed for intramitochondrial transcription and translation, including TFAM, TFBM1, and TFBM2.
25,26 A disruption of both nuclear and mitochondrial genes can therefore cause mitochondrial dysfunction and human disease (
table 1).
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