bims-cytox1 2024-09-08 papers

Mitochondrion. 2024 Sep 03. pii: S1567-7249(24)00110-7. [Epub ahead of print]79 101952

SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.

Chang-Lin Chen, Takaya Ishihara, Soumyadip Pal, Wei-Ling Huang, Emi Ogasawara, Chuang-Rung Chang, Naotada Ishihara.

Succinate dehydrogenase (SDH) plays pivotal roles in maintaining cellular metabolism, modulating regulatory control over both the tricarboxylic acid cycle and oxidative phosphorylation to facilitate energy production within mitochondria. Given that SDH malfunction may serve as a hallmark triggering pseudo-hypoxia signaling and promoting tumorigenesis, elucidating the impact of SDH assembly defects on mitochondrial functions and cellular responses is of paramount importance. In this study, we aim to clarify the role of SDHAF2, one assembly factor of SDH, in mitochondrial respiratory activities. To achieve this, we utilize the CRISPR/Cas9 system to generate SDHAF2 knockout in HeLa cells and examine mitochondrial respiratory functions. Our findings demonstrate a substantial reduction in oxygen consumption rate in SDHAF2 knockout cells, akin to cells with inhibited SDH activity. In addition, in our in-gel activity assays reveal a significant decrease not only in SDH activity but also in cytochrome c oxidase (COX) activity in SDHAF2 knockout cells. The reduced COX activity is attributed to the assembly defect and remains independent of SDH inactivation or SDH complex disassembly. Together, our results indicate a critical role of SDHAF2 in regulating respiration by facilitating the assembly of COX.

Keywords: Cytochrome c oxidase; Oxidative phosphorylation; Succinate dehydrogenase assembly factor 2 (SDHAF2)

DOI: https://doi.org/10.1016/j.mito.2024.101952

Endocr Connect. 2024 Aug 01. pii: EC-24-0221. [Epub ahead of print]

Endocrinological features and epileptic encephalopathy in COX deficiency due to SCO1 mutations: case series and review of literature.

Alessandro Barbato, Giulia Gori, Michele Sacchini, Francesca Pochiero, Sara Bargiacchi, Giovanna Traficante, Viviana Palazzo, Lucia Tiberi, Claudia Bianchini, Davide Mei, Elena Parrini, Tiziana Pisano, Elena Procopio, Renzo Guerrini, Angela Peron, Stefano Stagi.

CONTEXT: Cytochrome C oxidase (COX) is the fourth component of the respiratory chain and is located within the internal membrane of mitochondria. COX deficiency causes an inherited mitochondrial disease with significant genetic and phenotypic heterogeneity. Four clinical subtypes have been identified, each with distinct phenotypes and genetic variants. Mitochondrial complex IV deficiency nuclear type 4 (MC4DN4) is a form of COX deficiency associated with pathogenetic variants in the SCO1 gene.
CASE DESCRIPTION: We describe three patients with MC4DN4 with developmental and epileptic encephalopathy (DEE), hypopituitarism and SCO1 pathogenic variants. These patients' phenotypes considerably differ from previously reported MC4DN4 phenotypes as they associated DEE with progressive hypopituitarism and survival beyond the first months after birth. Pituitary deficiency in these patients progressively worsened and mainly involved growth hormone secretion and thyroid function.
CONCLUSIONS: Our findings expand knowledge of phenotypic variability in MC4DN4 and suggests that SCO1 is a candidate gene for genetic hypopituitarism and DEE.

DOI: https://doi.org/10.1530/EC-24-0221

Hum Mol Genet. 2024 Sep 03. 33(18): 1630-1641

Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases.

Sonia Figuccia, Rossella Izzo, Andrea Legati, Alessia Nasca, Paola Goffrini, Daniele Ghezzi, Camilla Ceccatelli Berti.

Aminoacyl-transfer RiboNucleic Acid synthetases (ARSs) are essential enzymes that catalyze the attachment of each amino acid to their cognate tRNAs. Mitochondrial ARSs (mtARSs), which ensure protein synthesis within the mitochondria, are encoded by nuclear genes and imported into the organelle after translation in the cytosol. The extensive use of next generation sequencing (NGS) has resulted in an increasing number of variants in mtARS genes being identified and associated with mitochondrial diseases. The similarities between yeast and human mitochondrial translation machineries make yeast a good model to quickly and efficiently evaluate the effect of variants in mtARS genes. Genetic screening of patients with a clinical suspicion of mitochondrial disorders through a customized gene panel of known disease-genes, including all genes encoding mtARSs, led to the identification of missense variants in WARS2, NARS2 and RARS2. Most of them were classified as Variant of Uncertain Significance. We exploited yeast models to assess the functional consequences of the variants found in these genes encoding mitochondrial tryptophanyl-tRNA, asparaginyl-tRNA, and arginyl-tRNA synthetases, respectively. Mitochondrial phenotypes such as oxidative growth, oxygen consumption rate, Cox2 steady-state level and mitochondrial protein synthesis were analyzed in yeast strains deleted in MSW1, SLM5, and MSR1 (the yeast orthologues of WARS2, NARS2 and RARS2, respectively), and expressing the wild type or the mutant alleles. Pathogenicity was confirmed for most variants, leading to their reclassification as Likely Pathogenic. Moreover, the beneficial effects observed after asparagine and arginine supplementation in the growth medium suggest them as a potential therapeutic approach.

Keywords: mitochondrial aminoacyl-tRNA synthetases; mitochondrial diseases; novel variants; yeast model

DOI: https://doi.org/10.1093/hmg/ddae104