bims-cytox1 2020-08-02 papers

Issue of 2020‒08‒02
four papers selected by
Gavin McStay
Staffordshire University

Biochim Biophys Acta Bioenerg. 2020 Jul 23. pii: S0005-2728(20)30125-0. [Epub ahead of print]1861(11): 148275

Clingy genes: Why were genes for ribosomal proteins retained in many mitochondrial genomes?

Lea Bertgen, Timo Mühlhaus, Johannes M Herrmann.

Why mitochondria still retain their own genome is a puzzle given the enormous effort to maintain a mitochondrial translation machinery. Most mitochondrially encoded proteins are membrane-embedded subunits of the respiratory chain. Their hydrophobicity presumably impedes their import into mitochondria. However, many mitochondrial genomes also encode protein subunits of the mitochondrial ribosome. These proteins lack transmembrane domains and hydrophobicity cannot explain why their genes remained in mitochondria. In this review, we provide an overview about mitochondrially encoded subunits of mitochondrial ribosomes of fungi, plants and protists. Moreover, we discuss and evaluate different hypotheses which were put forward to explain why (ribosomal) proteins remained mitochondrially encoded. It seems likely that the synthesis of ribosomal proteins in the mitochondrial matrix is used to regulate the assembly of the mitochondrial ribosome within mitochondria and to avoid problems that mitochondrial proteins might pose for cytosolic proteostasis and for the assembly of cytosolic ribosomes.

Keywords: Eukaryotes; Evolution; Gene transfer; Mitochondria; Respiratory chain; Ribosomes

DOI: https://doi.org/10.1016/j.bbabio.2020.148275

J Biol Chem. 2020 Jul 28. pii: jbc.RA120.014603. [Epub ahead of print]

Complex I mutations synergize to worsen the phenotypic expression of Leber's hereditary optic neuropathy.

Yanchun Ji, Juanjuan Zhang, Yuanyuan Lu, Qiuzi Yi, Mengquan Chen, Shipeng Xie, Xiaoting Mao, Yun Xiao, Feilong Meng, Minlian Zhang, Rulai Yang, Min-Xin Guan.

Leber's hereditary optic neuropathy (LHON) is a maternal inheritance of eye disease due to the mitochondrial DNA mtDNA) mutations. We previously discovered a 3866T>C mutation within the gene for the ND1 subunit of complex I as possibly amplifying disease progression for patients bearing the disease-causing 11778G>A mutation, within the gene for the ND4 subunit of Complex I. However, whether and how the ND1 mutation exacerbates the ND4 mutation were unknown. In this report, we showed that four Chinese families bearing both m.3866T>C and m.11778G>A mutations exhibited higher penetrances of LHON than 6 Chinese pedigrees carrying only the m.3866T>C mutation or families harboring only the m.11778G>A mutation. The protein structure analysis revealed that the m.3866T>C (I187T) and m.11778G>A (R340H) mutations destabilized the specific interactions with other residues of ND1 and ND4, thereby altering the structure and function of complex I, respectively. Cellular data obtained using cybrids constructed by transferring mitochondria from the Chinese families into mtDNA-less (ro) cells demonstrated that the mutations perturbed the stability, assembly and activity of complex I, leading to changes in mitochondrial ATP levels and membrane potential, and increasing the production of reactive oxygen species. These mitochondrial dysfunctions promoted the apoptotic sensitivity of cells and decreased mitophagy. Cybrids bearing only m.3866T>C mutation displayed mild mitochondrial dysfunctions while those harboring both m.3866T>C and m.11778G>A mutations exhibited greater mitochondrial dysfunctions. These suggested that the m.3866T>C mutation acted as the synergy with m.11778G>A mutation, aggravating mitochondrial dysfunctions contributing to higher penetrance of LHON in these families carrying both mtDNA mutations.

Keywords: Leber’s hereditary optic neuropathy; Modifier; NADH: ubiquinone oxidoreductase; apoptosis; human genetics; mitochondrial DNA; mitochondrial disease; mitochondrial respiratory chain complex; mitophagy; molecular modeling; organelle; oxygen radicals; pathogenesis; penetrance; vision

DOI: https://doi.org/10.1074/jbc.RA120.014603

Genes (Basel). 2020 Jul 26. pii: E855. [Epub ahead of print]11(8):

Novel NDUFA13 Mutations Associated with OXPHOS Deficiency and Leigh Syndrome: A Second Family Report.

Adrián González-Quintana, Inés García-Consuegra, Amaya Belanger-Quintana, Pablo Serrano-Lorenzo, Alejandro Lucia, Alberto Blázquez, Jorge Docampo, Cristina Ugalde, María Morán, Joaquín Arenas, Miguel A Martín.

Leigh syndrome (LS) usually presents as an early onset mitochondrial encephalopathy characterized by bilateral symmetric lesions in the basal ganglia and cerebral stem. More than 75 genes have been associated with this condition, including genes involved in the biogenesis of mitochondrial complex I (CI). In this study, we used a next-generation sequencing (NGS) panel to identify two novel biallelic variants in the NADH:ubiquinone oxidoreductase subunit A13 (NDUFA13) gene in a patient with isolated CI deficiency in skeletal muscle. Our patient, who represents the second family report with mutations in the CI NDUFA13 subunit, presented with LS lesions in brain magnetic resonance imaging, mild hypertrophic cardiomyopathy, and progressive spastic tetraparesis. This phenotype manifestation is different from that previously described in the first NDUFA13 family, which was predominantly characterized by neurosensorial symptoms. Both in silico pathogenicity predictions and oxidative phosphorylation (OXPHOS) functional findings in patient's skin fibroblasts (delayed cell growth, isolated CI enzyme defect, decreased basal and maximal oxygen consumption and as well as ATP production, together with markedly diminished levels of the NDUFA13 protein, CI, and respirasomes) suggest that these novel variants in the NDUFA13 gene are the underlying cause of the CI defect, expanding the genetic heterogeneity of LS.

Keywords: Leigh syndrome; NDUFA13 gene; OXPHOS assembly; OXPHOS diagnosis; mitochondrial OXPHOS dysfunction; mitochondrial complex I deficiency

DOI: https://doi.org/10.3390/genes11080855

Nature. 2020 Jul 29.

Na+ controls hypoxic signalling by the mitochondrial respiratory chain.

All metazoans depend on the consumption of O2 by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O2 to produce reactive oxygen species that can drive cell adaptations1-4, a phenomenon that occurs in hypoxia4-8 and whose precise mechanism remains unknown. Ca2+ is the best known ion that acts as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential10. Here we show that Na+ acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I during acute hypoxia11 drives acidification of the matrix and the release of free Ca2+ from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na+/Ca2+ exchanger promotes the import of Na+ into the matrix. Na+ interacts with phospholipids, reducing inner mitochondrial membrane fluidity and the mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III. The inhibition of Na+ import through the Na+/Ca2+ exchanger is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism.

DOI: https://doi.org/10.1038/s41586-020-2551-y