MTO1 mediates tissue specificity of OXPHOS defects via tRNA modification and translation optimization, which can be bypassed by dietary intervention.

Mitochondrial diseases often exhibit tissue-specific pathologies, but this phenomenon is poorly understood. Here we present regulation of mitochondrial translation by the Mitochondrial Translation Optimization Factor 1, MTO1, as a novel player in this scenario. We demonstrate that MTO1 mediates tRNA modification and controls mitochondrial translation rate in a highly tissue-specific manner associated with tissue-specific OXPHOS defects. Activation of mitochondrial proteases, aberrant translation products, as well as defects in OXPHOS complex assembly observed in MTO1 deficient mice further imply that MTO1 impacts translation fidelity. In our mouse model, MTO1-related OXPHOS deficiency can be bypassed by feeding a ketogenic diet. This therapeutic intervention is independent of the MTO1-mediated tRNA modification and involves balancing of mitochondrial and cellular secondary stress responses. Our results thereby establish mammalian MTO1 as a novel factor in the tissue-specific regulation of OXPHOS and fine tuning of mitochondrial translation accuracy.

Microfluidic Synthesis of Magnetite Nanoparticles for the Controlled Release of Antibiotics.

Magnetite nanoparticles (MNPs) have been intensively studied for biomedical applications, especially as drug delivery systems for the treatment of infections. Additionally, they are characterized by intrinsic antimicrobial properties owing to their capacity to disrupt or penetrate the microbial cell wall and induce cell death. However, the current focus has shifted towards increasing the control of the synthesis reaction to ensure more uniform nanoparticle sizes and shapes. In this context, microfluidics has emerged as a potential candidate method for the controlled synthesis of nanoparticles. Thus, the aim of the present study was to obtain a series of antibiotic-loaded MNPs through a microfluidic device. The structural properties of the nanoparticles were investigated through X-ray diffraction (XRD) and, selected area electron diffraction (SAED), the morphology was evaluated through transmission electron microscopy (TEM) and high-resolution TEM (HR-TEM), the antibiotic loading was assessed through Fourier-transform infrared spectroscopy (FT-IR) and, and thermogravimetry and differential scanning calorimetry (TG-DSC) analyses, and. the release profiles of both antibiotics was determined through UV-Vis spectroscopy. The biocompatibility of the nanoparticles was assessed through the MTT assay on a BJ cell line, while the antimicrobial properties were investigated against the S. aureus, P. aeruginosa, and C. albicans strains. Results proved considerable uniformity of the antibiotic-containing nanoparticles, good biocompatibility, and promising antimicrobial activity. Therefore, this study represents a step forward towards the microfluidic development of highly effective nanostructured systems for antimicrobial therapies.

MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy.

Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1) were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients.