bims-cytox1 2019-03-31 papers

Issue of 2019–03–31
three papers selected by
Gavin McStay, Staffordshire University

Ann Clin Transl Neurol. 2019 Mar;6(3): 515-524

Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis.

Objectives: Mitochondrial methionyl-tRNA formyltransferase (MTFMT) is required for the initiation of translation and elongation of mitochondrial protein synthesis. Pathogenic variants in MTFMT have been associated with Leigh syndrome (LS) and mitochondrial multiple respiratory chain deficiencies. We sought to elucidate the spectrum of clinical, neuroradiological and molecular genetic findings of patients with bi-allelic pathogenic variants in MTFMT.
Methods: Retrospective cohort study combining new cases and previously published cases.
Results: Thirty-eight patients with pathogenic variants in MTFMT were identified, including eight new cases. The median age of presentation was 14 months (range: birth to 17 years, interquartile range [IQR] 4.5 years), with developmental delay and motor symptoms being the most frequent initial manifestation. Twenty-nine percent of the patients survived into adulthood. MRI headings in MTFMT pathogenic variants included symmetrical basal ganglia changes (62%), periventricular and subcortical white matter abnormalities (55%), and brainstem lesions (48%). Isolated complex I and combined respiratory chain deficiencies were identified in 31% and 59% of the cases, respectively. Reduction of the mitochondrial complex I and complex IV subunits was identified in the fibroblasts (13/13). Sixteen pathogenic variants were identified, of which c.626C>T was the most common. Seventy-four percent of the patients were alive at their last clinical review (median 6.8 years, range: 14 months to 31 years, IQR 14.5 years).
Interpretation: Patients that harbour pathogenic variants in MTFMT have a milder clinical phenotype and disease progression compared to LS caused by other nuclear defects. Fibroblasts may preclude the need for muscle biopsy, to prove causality of any novel variant.

DOI: https://doi.org/10.1002/acn3.725

J Biol Chem. 2019 Mar 25. pii: jbc.RA118.005355. [Epub ahead of print]

Yeast mitochondrial protein Pet111p binds directly to two distinct targets in COX2 mRNA, suggesting a mechanism of translational activation.

Julia L Jones, Katharina B Hofmann, Andrew T Cowan, Dmitry Temiakov, Patrick Cramer, Michael Anikin.

The genes in mitochondrial DNA code for essential subunits of the respiratory chain complexes. In yeast, expression of mitochondrial genes is controlled by a group of gene-specific translational activators encoded in the nucleus. These factors appear to be part of a regulatory system that enables concerted expression of the necessary genes from both nuclear and mitochondrial genomes to produce functional respiratory complexes. Many of the translational activators are believed to act on the 5'-untranslated regions of target mRNAs, but the molecular mechanisms involved in this regulation remain obscure. In this study, we used a combination of in vivo and in vitro analyses to characterize the interactions of one of these translational activators, the pentatricopeptide repeat (PPR) protein Pet111p, with its presumed target, COX2 mRNA, which encodes subunit II of cytochrome c oxidase. Using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis, we found that Pet111p binds directly and specifically to a 5'-end proximal region of the COX2 transcript. Further, we applied in vitro RNase footprinting and mapped two binding targets of the protein, one of which is located in the 5'-untranslated leader and the other within the coding sequence. Combined with available genetic data, these results suggest a plausible mechanism of translational activation, in which binding of Pet111p may prevent inhibitory secondary structures from forming in the translation initiation region, thus rendering the mRNA available for interaction with the ribosome.

Keywords: PAR-CLIP; RNA-protein interaction; cytochrome c oxidase (Complex IV); gene expression; mitochondria; pentatricopeptide repeat (PPR) protein; respiratory complex; translation regulation; translational activator

DOI: https://doi.org/10.1074/jbc.RA118.005355

Mitochondrion. 2019 Mar 26. pii: S1567-7249(18)30187-9. [Epub ahead of print]

The first direct activity assay for the mitochondrial protease OMA1.

Julia Tobacyk, Nirmala Parajuli, Stephen Shrum, John P Crow, Lee Ann MacMillan-Crow.

Mitochondria continually undergo fission and fusion which allow mitochondria to rapidly change their shape, size, and function throughout the cell life cycle. OMA1, a zinc metalloproteinase enzyme, is a key regulator of the mitochondrial fusion machinery. The paucity of information regarding OMA1 regulation and function largely stems from the fact that there is no direct method to quantitatively measure its activity. Using a fluorescence-based reporter assay, we developed a sensitive method to measure OMA1 enzymatic activity in whole cell lysates.

Keywords: Fluorescence-based reporter; Fusion; Mitochondria; OMA1; Proteases

DOI: https://doi.org/10.1016/j.mito.2019.03.001