Mitochondria, the powerhouses of the cell, contain their own ribosomes, which specialize in synthesizing a handful of proteins (8 in yeast, 13 in human cells). These proteins are required for the generation of chemical energy in the form of adenosine triphosphate (ATP) by the process of oxidative phosphorylation. Despite the biological relevance of the mitoribosomes, knowledge about the molecular details of the assembly pathway and factors involved in their biogenesis is still very limited.
In a study published in the November 5 issue of the journal Cell Metabolism, a group of Miller School scientists led by Antoni Barrientos, Ph.D., professor of neurology and biochemistry and molecular biology, used yeast models to characterize a protein called Mrh4 as the first DEAD-box protein involved in the process of mitoribosome biogenesis. The researchers include Flavia Fontanesi, Ph.D., research assistant professor of biochemistry and molecular biology, and Dasmanthie De Silva, a Ph.D. student from the Biochemistry and Molecular Biology program.
DEAD-box proteins are enzymes that rearrange RNA and RNA-protein structures. These proteins have roles in every aspect of RNA biology, yet are not well understood. Barrientos and his team identified Mrh4 as the mitochondrial DEAD-box protein of a yeast, Saccharomyces cerevisiae, as being essential for large mitoribosome subunit biogenesis.
S. cerevisiae mitochondria have one particular ribosome, 74S, consisting of a small 37S subunit and a large 54S subunit. The large subunit is made up of a 21S ribosome RNA (rRNA) and at least 44 proteins. Barrientos and his team demonstrated that the protein Mrh4 interacts with the ribosomal 21S RNA of the 54S large subunit to promote its assembly. They created Mrh4 knockout strains and showed that without Mrh4, the 21S rRNA matures and forms part of a late-stage assembly intermediate missing key proteins Mrpl16 and Mrpl39.
The biomedical importance of the mitoribosomes is highlighted by the fact that mutations in most mitochondrial-DNA-encoded transfer-RNAs as well as in nuclear genes encoding mitochondrial ribosome proteins are responsible for infantile multi-systemic diseases frequently involving encephalomyopathy and hypertrophic cardiomyopathy.
The yeast Mrh4 protein has a human homologue whose function is currently being characterized in Barrientos’ laboratory. The human protein could be a new candidate when screening for mutations responsible for human encephalomyopathies and cardiomyopathies associated with mitochondrial protein synthesis defects.
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