bims-cytox1 2022-04-24 papers

Issue of 2022–04–24
three papers selected by
Gavin McStay, Staffordshire University

Nat Rev Genet. 2022 Apr 22.

Organization and expression of the mammalian mitochondrial genome.

The mitochondrial genome encodes core subunits of the respiratory chain that drives oxidative phosphorylation and is, therefore, essential for energy conversion. Advances in high-throughput sequencing technologies and cryoelectron microscopy have shed light on the structure and organization of the mitochondrial genome and revealed unique mechanisms of mitochondrial gene regulation. New animal models of impaired mitochondrial protein synthesis have shown how the coordinated regulation of the cytoplasmic and mitochondrial translation machineries ensures the correct assembly of the respiratory chain complexes. These new technologies and disease models are providing a deeper understanding of mitochondrial genome organization and expression and of the diseases caused by impaired energy conversion, including mitochondrial, neurodegenerative, cardiovascular and metabolic diseases. They also provide avenues for the development of treatments for these conditions.

DOI: https://doi.org/10.1038/s41576-022-00480-x

Int J Mol Sci. 2022 Apr 08. pii: 4149. [Epub ahead of print]23(8):

Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.

Liza Douiev, Chaya Miller, Guy Keller, Hadar Benyamini, Bassam Abu-Libdeh, Ann Saada.

Cytochrome c oxidase (COX), a multimeric protein complex, is the final electron acceptor in the mitochondrial electron transfer chain. Primary COX deficiency, caused by mutations in either mitochondrial DNA or nuclear-encoded genes, is a heterogenous group of mitochondrial diseases with a wide range of presentations, ranging from fatal infantile to subtler. We previously reported a patient with primary COX deficiency due to a pathogenic variant in COX4I1 (encoding the common isoform of COX subunit 4, COX4-1), who presented with bone marrow failure, genomic instability, and short stature, mimicking Fanconi anemia (FA). In the present study, we demonstrated that accumulative DNA damage coincided primarily with proliferative cells in the patient's fibroblasts and in COX4i1 knockdown cells. Expression analysis implicated a reduction in DNA damage response pathways, which was verified by demonstrating impaired recovery from genotoxic insult and decreased DNA repair. The premature senescence of the COX4-1-deficient cells prevented us from undertaking additional studies; nevertheless, taken together, our results indicate replicative stress and impaired nuclear DNA damage response in COX4-1 deficiency. Interestingly, our in vitro findings recapitulated the patient's presentation and present status.

Keywords: COX4i1; DNA damage; cytochrome c oxidase; mitochondria; mitochondrial respiratory chain; replicative stress

DOI: https://doi.org/10.3390/ijms23084149

Antioxidants (Basel). 2022 Apr 08. pii: 741. [Epub ahead of print]11(4):

Multicentric Standardization of Protocols for the Diagnosis of Human Mitochondrial Respiratory Chain Defects.

Nuria Bujan, Constanza Morén, Francesc J García-García, Alberto Blázquez, Clara Carnicer, Ana Belén Cortés, Cristina González, Ester López-Gallardo, Ester Lozano, Sonia Moliner, Laura Gort, Ester Tobías, Aitor Delmiro, Miguel Ángel Martin, Miguel Ángel Fernández-Moreno, Eduardo Ruiz-Pesini, Elena Garcia-Arumí, Juan Carlos Rodríguez-Aguilera, Glòria Garrabou.

The quantification of mitochondrial respiratory chain (MRC) enzymatic activities is essential for diagnosis of a wide range of mitochondrial diseases, ranging from inherited defects to secondary dysfunctions. MRC lesion is frequently linked to extended cell damage through the generation of proton leak or oxidative stress, threatening organ viability and patient health. However, the intrinsic challenge of a methodological setup and the high variability in measuring MRC enzymatic activities represents a major obstacle for comparative analysis amongst institutions. To improve experimental and statistical robustness, seven Spanish centers with extensive experience in mitochondrial research and diagnosis joined to standardize common protocols for spectrophotometric MRC enzymatic measurements using minimum amounts of sample. Herein, we present the detailed protocols, reference ranges, tips and troubleshooting methods for experimental and analytical setups in different sample preparations and tissues that will allow an international standardization of common protocols for the diagnosis of MRC defects. Methodological standardization is a crucial step to obtain comparable reference ranges and international standards for laboratory assays to set the path for further diagnosis and research in the field of mitochondrial diseases.

Keywords: diagnosis; enzyme activity; mitochondrial disease; mitochondrial respiratory chain; standardization

DOI: https://doi.org/10.3390/antiox11040741