bims-cytox1 2024-12-08 papers

Am J Med Genet A. 2024 Dec 05. e63947

SURF1 Deficiency: Expanding on Disease Phenotype and Assessing Disease Burden by Describing Clinical and Biochemical Phenotype.

Saima Kayani, Victor Daescu, Hamza Dahshi, Souad Messahel, Kasey Woleban, Berge A Minassian, Qinglan Ling, Steven J Gray.

Leigh syndrome, a severe neurological disorder is commonly caused by homozygous or bi-allelic pathogenic variants in the SURF1 gene. SURF1 deficiency leads to dysfunction of Cytochrome C Oxidase (COX) activity, which is crucial for mitochondrial oxidative phosphorylation. Understanding COX activity's correlation with disease severity is essential for developing SURF1 Leigh Syndrome biomarkers. This study assesses the disease burden in SURF1 Leigh Syndrome and evaluates COX activity as a treatment biomarker. We reviewed records and questionnaires from 17 individuals, classifying them into phenotypic and genotypic groups. We compared COX activity assays in patient fibroblasts to age-matched controls, clinical data, and neuroimaging findings. Patient COX activity was at most 50% of controls, averaging 32% (p < 0.001). Common clinical features included brainstem abnormalities (93.3%), motor regression (92.3%), bi-allelic heterozygous SURF1 variants (88.2%), and delayed growth/development (35.7%). Homozygous and heterozygous nonsense/frameshift variants showed more severe phenotypes (p = 0.008) and more MRI abnormalities (p = 0.005). Significant COX activity reduction is linked to SURF1 Leigh Syndrome, with genotype influencing disease severity. Clinical and neuroimaging correlations show potential for prognostic indicators. This study lays the groundwork for future research and clinical application of COX activity as a SURF1 Leigh Syndrome biomarker.

Keywords: Leigh syndrome; SURF1 gene; biomarkers; cytochrome C oxidase; mitochondrial disorders; neuroimaging

DOI: https://doi.org/10.1002/ajmg.a.63947

J Biomed Opt. 2024 Nov;29(11): 117001

Understanding metabolic responses to forearm arterial occlusion measured with two-channel broadband near-infrared spectroscopy.

Fiza Saeed, Caroline Carter, John Kolade, Robert Matthew Brothers, Hanli Liu.

Significance: Broadband near-infrared spectroscopy (bbNIRS) is useful for the quantification of cerebral metabolism. However, its usefulness has not been explored for broad biomedical applications.
Aim: We aimed to quantify the dynamic responses of oxidized cytochrome c oxidase ( Δ[oxCCO] ) within the mitochondria to arterial occlusion and the dynamic correlations between hemodynamic ( Δ[HbO] ) and Δ[oxCCO] responses during and after occlusion in forearm tissues.
Approach: We recruited 14 healthy participants with two-channel bbNIRS measurements in response to a 5-min forearm arterial occlusion. The bbNIRS system consisted of one shared white-light source and two spectrometers. The modified Beer-Lambert law was applied to determine the occlusion-induced changes in Δ[oxCCO] and Δ[HbO] in the shallow- and deep-tissue layers.
Results: During the 5-min occlusion, dynamic responses in hemodynamics exhibited the expected changes, but Δ[oxCCO] remained constant, as observed in the 1- and 3-cm channels. A linear correlation between Δ[HbO] and Δ[oxCCO] was observed only during the recovery phase, with a stronger correlation in deeper tissues. The observation of a constant Δ[oxCCO] during the cuff period was consistent with two previous reports. The interpretation of this observation is based on the literature that the oxygen metabolism of the skeletal muscle during arterial occlusion remains unchanged before all oxy-hemoglobin (and oxy-myoglobin) resources are completely depleted. Because a 5-min arterial occlusion is not adequate to exhaust all oxygen supply in the vascular bed of the forearm, the local oxygen supply to the muscle mitochondria maintains redox metabolism uninterrupted by occlusion.
Conclusions: We provide a better understanding of the mitochondrial responses to forearm arterial occlusion and demonstrate the usefulness of bbNIRS.

Keywords: arterial occlusion; broadband near-infrared spectroscopy; cytochrome c oxidase; metabolic activity; oxygenated hemoglobin

DOI: https://doi.org/10.1117/1.JBO.29.11.117001

ACS Synth Biol. 2024 Dec 04.

Toward a Quadruplet Codon Mitochondrial Genetic Code.

Michael L Pigula, Yahui Ban, Peter G Schultz.

Nature has evolved to exclusively use a genetic code consisting of triplet nucleotide codons. The translation system, however, is known to be compatible with 4-nucleotide frameshift or quadruplet codons. In this study, we begin to explore the possibility of a genome made up entirely of quadruplet codons using the minimal mitochondrial genome of Saccharomyces cerevisiae as a model system. We demonstrate that mitochondrial tryptophanyl- and tyrosyl-tRNAs with modified anticodons effectively suppress mutant cox3 genes containing a TAG stop or TAGA quadruplet codon, leading to the production of full-length COX3 and a respiratory-competent phenotype. This work provides a method for introducing heterologous tRNAs into the yeast mitochondria for genetic engineering applications and serves as a starting point for the development of a quadruplet codon genetic code.

Keywords: genome recoding; mitochondria; quadruplet codon; tRNA engineering

DOI: https://doi.org/10.1021/acssynbio.4c00630