bims-cytox1 2019-08-11 papers

Issue of 2019–08–11
two papers selected by
Gavin McStay, Staffordshire University

Drugs Context. 2019 ;8 212588

Mitochondrial disorders and drugs: what every physician should know.

Daniele Orsucci, Elena Caldarazzo Ienco, Gabriele Siciliano, Michelangelo Mancuso.

Mitochondrial disorders are a group of metabolic conditions caused by impairment of the oxidative phosphorylation system. There is currently no clear evidence supporting any pharmacological interventions for most mitochondrial disorders, except for coenzyme Q10 deficiencies, Leber hereditary optic neuropathy, and mitochondrial neurogastrointestinal encephalomyopathy. Furthermore, some drugs may potentially have detrimental effects on mitochondrial dysfunction. Drugs known to be toxic for mitochondrial functions should be avoided whenever possible. Mitochondrial patients needing one of these treatments should be carefully monitored, clinically and by laboratory exams, including creatine kinase and lactate. In the era of molecular and 'personalized' medicine, many different physicians (not only neurologists) should be aware of the basic principles of mitochondrial medicine and its therapeutic implications. Multicenter collaboration is essential for the advancement of therapy for mitochondrial disorders. Whenever possible, randomized clinical trials are necessary to establish efficacy and safety of drugs. In this review we discuss in an accessible way the therapeutic approaches and perspectives in mitochondrial disorders. We will also provide an overview of the drugs that should be used with caution in these patients.

Keywords: coenzyme Q10; drugs; mitochondria; mitochondrial diseases; mtDNA; toxicity

DOI: https://doi.org/10.7573/dic.212588

Nucleic Acids Res. 2019 Aug 09. pii: gkz684. [Epub ahead of print]

C6orf203 is an RNA-binding protein involved in mitochondrial protein synthesis.

Shreekara Gopalakrishna, Sarah F Pearce, Adam M Dinan, Florian A Schober, Miriam Cipullo, Henrik Spåhr, Anas Khawaja, Camilla Maffezzini, Christoph Freyer, Anna Wredenberg, Ilian Atanassov, Andrew E Firth, Joanna Rorbach.

In all biological systems, RNAs are associated with RNA-binding proteins (RBPs), forming complexes that control gene regulatory mechanisms, from RNA synthesis to decay. In mammalian mitochondria, post-transcriptional regulation of gene expression is conducted by mitochondrial RBPs (mt-RBPs) at various stages of mt-RNA metabolism, including polycistronic transcript production, its processing into individual transcripts, mt-RNA modifications, stability, translation and degradation. To date, only a handful of mt-RBPs have been characterized. Here, we describe a putative human mitochondrial protein, C6orf203, that contains an S4-like domain-an evolutionarily conserved RNA-binding domain previously identified in proteins involved in translation. Our data show C6orf203 to bind highly structured RNA in vitro and associate with the mitoribosomal large subunit in HEK293T cells. Knockout of C6orf203 leads to a decrease in mitochondrial translation and consequent OXPHOS deficiency, without affecting mitochondrial RNA levels. Although mitoribosome stability is not affected in C6orf203-depleted cells, mitoribosome profiling analysis revealed a global disruption of the association of mt-mRNAs with the mitoribosome, suggesting that C6orf203 may be required for the proper maturation and functioning of the mitoribosome. We therefore propose C6orf203 to be a novel RNA-binding protein involved in mitochondrial translation, expanding the repertoire of factors engaged in this process.

DOI: https://doi.org/10.1093/nar/gkz684