Abstract
Biogenesis of respiratory chain complexes depends on the expression of mitochondrial-encoded subunits. Their synthesis occurs on membrane-associated ribosomes and is probably coupled to their membrane insertion. Defects in expression of mitochondrial translation products are among the major causes of mitochondrial disorders. Mdm38 is related to Letm1, a protein affected in Wolf-Hirschhorn syndrome patients. Like Mba1 and Oxa1, Mdm38 is an inner membrane protein that interacts with ribosomes and is involved in respiratory chain biogenesis. We find that simultaneous loss of Mba1 and Mdm38 causes severe synthetic defects in the biogenesis of cytochrome reductase and cytochrome oxidase. These defects are not due to a compromised membrane binding of ribosomes but the consequence of a mis-regulation in the synthesis of Cox1 and cytochrome b. Cox1 expression is restored by replacing Cox1-specific regulatory regions in the mRNA. We conclude, that Mdm38 and Mba1 exhibit overlapping regulatory functions in translation of selected mitochondrial mRNAs.
Highlights
Cells of animals or fungi contain two translation machineries, one in the cytosol and one in mitochondria
The results shown in this study strongly support this idea because the simultaneous deletion of both proteins leads to severe synthetic defects in the biogenesis of mitochondrial translation products
We show that Mdm38 and Mba1 play a critical and selective role in the regulation of mitochondrial translation of COX1 and CYTB mRNA
Summary
Cells of animals or fungi contain two translation machineries, one in the cytosol and one in mitochondria. Whereas the cytosolic translation machinery is well characterized, the process by which mitochondrial ribosomes synthesize proteins is still illdefined. In Saccharomyces cerevisiae, only eight proteins are encoded by the mitochondrial genome: subunits 1–3 of cytochrome oxidase (Cox, Cox, and Cox3); cytochrome b (Cyt b) of cytochrome reductase; subunits 6, 8, and 9 of the FoF1ATPase (Atp, Atp, and Atp9); and the ribosomal subunit Var. The specialization on the synthesis of a small number of hydrophobic membrane proteins might explain why the mitochondrial translation system—in contrast to that of the cytosol—is intimately associated with the inner membrane. Even mRNAs are bound to the inner membrane because of the presence of membrane-associated translational activators, which bind to 5Ј untranslated regions of the mRNAs (Michaelis et al, 1991; Fox, 1996).
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