Novel strategy for studying mitoribosomal and mitochondrial impact on disease

By Samantha Black, PhD, ScienceBoard editor in chief

November 5, 2019 -- Researchers from the Karolinska Institutet in Sweden have developed a new experimental tool for studying mitochondrial protein synthesis in vivo. This research is presented in the October 5 issue of Cell Reports.

As semi-autonomous eukaryotic cell organelles, mitochondria carry out important cellular processes such as oxidative phosphorylation. They contain mtDNA in a compact circular genome and in order to synthesize this mtDNA, mitochondria contain specialized ribosomes, called mitoribosomes that are 55 S ribonucleoprotein complexes with two subunits. Mitoribosomes were first discovered in 1967 and many studies have been conducted to try to understand their structure and function. However, essential knowledge about the proteins coordinating translation and mitoribosomal assembly are still missing. This may be, in part, due to the lack of relevant animal models.

Proper regulation of mitochondrial function is crucial for maintaining health. It is well-established that decreased mitochondrial function plays a key role in ageing and age-associated human diseases. There are also a number of inherited mitochondrial disorders that can result in impaired function of the brain, heart, skeletal muscle, and other organs.

"It is crucial to unravel how mitochondrial function is regulated in order to better understand these disorders and develop new treatment strategies," says Nils-Göran Larsson, professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet, who led the study.

Researchers wanted to gain new insights into regulatory mechanisms of mitochondrial translation in tissues and mutations in rRNAs and mitoribosomal proteins that can cause severe tissue-specific human diseases. They presented a new model, called MitoRibo-Tag mice, as a versatile tool to study mitoribosome composition and the mitoribosome-interactome (the whole set of molecular interactions) in different mouse tissues in vivo. They used the tool to enable enabling affinity purification and proteomics analyses of mitoribosomes and their interactome in the heart, liver and kidneys.

Mitoribosome isolated from tissues of MitoRibo-Tag mice were tagged by co-immunoprecipitation, which allowed researchers to identify proteins by quantitative liquid-chromatography mass spectrometry and interaction proteomics using the MitoCarta database and differential abundance.

The researchers identified all 82 proteins that make up the mitochondrial ribosome by quantification, as well as a large number of associated factors including mitoribosome-interacting proteins (MIPs) revealing a complex network of orphan and known mitochondrial protein interactions with the mitoribosome. Some of the identified factors are novel mitochondrial proteins of unknown function that may have important roles in controlling mitochondrial protein synthesis. The researchers suggest that the MitoRibo-Tag mouse model is appropriate for discovering orphan MIPs and unknown interactions which may occur is metabolic disorders and during disturbed mitochondrial translation.

"We believe that the MitoRibo-Tag mice will be a valuable tool for future studies of how mitochondrial protein synthesis is affected by disease, pharmacological interventions, ageing and different physiological situations such as exercise, caloric restriction and high-fat diet," says Miriam Cipullo, PhD student at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, and co-author of the paper.

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