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, 48 (100), 77-84

Mitochondria: Impaired Mitochondrial Translation in Human Disease


Mitochondria: Impaired Mitochondrial Translation in Human Disease

Veronika Boczonadi et al. Int J Biochem Cell Biol.


Defects of the mitochondrial protein synthesis cause a subgroup of mitochondrial diseases, which are usually associated with decreased activities of multiple respiratory chain (RC) enzymes. The clinical presentations of these disorders are often disabling, progressive or fatal, affecting the brain, liver, skeletal muscle, heart and other organs. Currently there are no effective cures for these disorders and treatment is at best symptomatic. The diagnosis in patients with multiple respiratory chain complex defects is particularly difficult because of the massive number of nuclear genes potentially involved in intra-mitochondrial protein synthesis. Many of these genes are not yet linked to human disease. Whole exome sequencing rapidly changed the diagnosis of these patients by identifying the primary defect in DNA, and preventing the need for invasive and complex biochemical testing. Better understanding of the mitochondrial protein synthesis apparatus will help us to explore disease mechanisms and will provide clues for developing novel therapies.

Keywords: Cytosolic translation; Human mitochondrial disease; Mitochondrial respiratory chain; Mitochondrial translation; Tissue specific presentation.


Fig. 1
Fig. 1
Schematic overview of human genes involved in mitochondrial protein synthesis defects. Prior to mitochondrial protein synthesis the mtDNA needs to be maintained and correctly replicated and transcribed. Mutations within nDNA-encoded genes responsible for these functions lead to mtDNA deletion(s) and depletion. Several other proteins also have to be imported into the mitochondria for accurate mitochondrial translation processes. These nuclear encoded genes are categorised into different groups based on their role in the translational machinery. The first group of genes (highlighted in red) are the genes that are involved in cytosolic translation. Some of these nuclear genes (GARS, KARS (marked with black stars)) are transported to the mitochondria and also function as mitochondrial aminoacyl t-RNA synthetase (ARS). Nuclear genes involved in mt-tRNA modification are: MTO1, PUS1, TRMU and MTFMT (highlighted in purple) (the functions of the genes are shown and labelled as (1). Up to date 10 mitochondrial ARSs have been found to cause translational deficiencies in humans. These genes are DARS2, RARS2, EARS2, MARS2, FARS2, AARS2, YARS2, SARS2, HARS2 and LARS2 (highlighted in dark blue) (2). Nuclear genes encoding for ribosomal proteins and involved in impaired mitochondrial translation are MRPL3, MRPS16, MRPS22, MRPL12 and MRPL44 (light blue) (3). Genes represented in green are responsible for the mitochondrial translation steps: initiation, elongation and termination (4): RMND1, TUFM, TSFM, GFM1, C12orf65. Nuclear genes such as translational activators and mRNA stability factors (LRPPRC, TACO1 and MTPAP) also involved in impaired mitochondrial protein synthesis (5). For the formation of the respiratory chain (RC) complexes both nuclear and mitochondrial DNA are required. nDNA-encoded RC subunit genes and RC assembly factors need to be synthetised, transported to the mitochondrial matrix and assembled into functional enzyme complexes with the 13 mDNA-encoded proteins. These 13 proteins are represented within each complex (CI: ND1, ND2, ND3, ND 4L, ND4, ND5, ND6; CIII: CYTB; CIV: COX1, COX2, COX3; CV: ATPase6, ATPase8) (6). Schematic drawing of the mitochondrial genome (7) showing the 13 proteins, 2 r-RNA, 22 t-RNA regions and the control region. Mutations for MELAS, MERRF and for common deletions are shown in the diagram. Associated clinical phenotypes with the gene mutations mentioned above are detailed in Table 1.

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