bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2025–09–07
two papers selected by
Gavin McStay, Liverpool John Moores University
  1. Insights into the translational activation mechanisms of the COX1 mRNA in yeast mitochondria.
  2. Improved AAV9-based gene therapy design for SURF1-related Leigh syndrome with minimal toxicity.
  1. J Cell Sci. 2025 Aug 15. pii: jcs263694. [Epub ahead of print]138(16):
    Insights into the translational activation mechanisms of the COX1 mRNA in yeast mitochondria.
    Angelica Zamudio-Ochoa, Yolanda Camacho-Villasana, Ulrik Pedroza-Dávila, Aldo E García-Guerrero, Xochitl Pérez-Martínez.
      Mitochondrial translation is a crucial regulatory step in mitochondrial genome expression. In Saccharomyces cerevisiae, translational activators are believed to bind to the 5' UTRs of their target mRNAs to position the mitochondrial ribosome at the start codon. Pet309 and Mss51 are translational activators of COX1 mRNA, which encodes subunit one of cytochrome c oxidase. Pet309 physically interacts with COX1 mRNA, but no direct interaction of Mss51 with its target mRNA has been detected. Currently, the mechanisms underlying translational activation of COX1, or any other mitochondrial gene, remain poorly understood. To explore in depth the mechanism of COX1 mRNA translational activation, we studied the association of Pet309 and Mss51 with the mitochondrial ribosome. Both Pet309 and Mss51 interact with the mitoribosome regardless of the presence of COX1 mRNA or of each other. The association of Pet309 with the ribosome and with COX1 mRNA depends on its N-terminal domain. These findings indicate that Pet309 and Mss51 stably interact with the mitoribosome independently of active translation. By integrating our data with previously published research, we propose a new mechanism of COX1 mRNA translation activation.
    Keywords:   COX1 mRNA; Mitochondria; Mitoribosome; Mss51; Pet309; Translation
    DOI:  https://doi.org/10.1242/jcs.263694
  2. Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101554
    Improved AAV9-based gene therapy design for SURF1-related Leigh syndrome with minimal toxicity.
    Qinglan Ling, Matthew Rioux, Harrison Higgs, Yuhui Hu, Scarlett E Dwyer, Steven J Gray.
      Surfeit locus protein 1 (SURF1)-related Leigh syndrome is an early-onset neurodegenerative disorder characterized by a reduction in complex IV activity that disrupts mitochondrial function. Currently, there are no disease-modifying treatments available. Previously, we reported that a gene replacement therapy for SURF1-related Leigh syndrome was developed, which showed improved complex IV activity and restored exercise-induced lactate acidosis, as well as a high safety profile in wild-type (WT) mice. However, further investigations of this original SURF1 vector design uncovered cytotoxicity in multiple tissues of WT rats despite having minimal immune responses. We hypothesized that this cytotoxicity was elicited by SURF1 protein overexpression driven by a strong ubiquitous promoter, CBh. Here, we report the development of an improved gene therapy for SURF1 Leigh syndrome by utilizing a different promoter and polyadenylation sequence. Our data showed that, with lower SURF1 protein expression, the new design conferred a similar level of efficacy, but with minimal cytotoxicity in mice or rats. We propose this new vector design as a promising therapeutic candidate for SURF1-related Leigh syndrome, warranting further translational studies.
    Keywords:  AAV; Leigh syndrome; SURF1; adeno-associated virus; gene replacement therapy; gene therapy; mitochondrial diseases; overexpression toxicity
    DOI:  https://doi.org/10.1016/j.omtm.2025.101554
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