bims-cytox1 2019-07-21 papers

Issue of 2019–07–21
five papers selected by
Gavin McStay, Staffordshire University

Mol Biol Cell. 2019 Jul 18. mbcE18120788

Key within-membrane residues and precursor dosage impact the allotopic expression of yeast subunit II of cytochrome c oxidase.

Diana Rubalcava-Gracia, Juan García-Rincón, Ruy Pérez-Montfort, Patrice Paul Hamel, Diego González-Halphen.

Experimentally relocating mitochondrial genes to the nucleus for functional expression (allotopic expression) is a challenging process. The high hydrophobicity of mitochondria-encoded proteins seems to be one of the main factors preventing this allotopic expression. We focused on subunit II of cytochrome c oxidase (Cox2) to study which modifications may enable or improve its allotopic expression in yeast. Cox2 can be imported from the cytosol into mitochondria in the presence of the W56R substitution, which decreases the protein hydrophobicity and allows partial respiratory rescue of a cox2-null strain. We show that the inclusion of a positive charge is more favorable over substitutions that only decrease the hydrophobicity. We also searched for other determinants enabling allotopic expression in yeast by examining the COX2 gene in organisms where it was transferred to the nucleus during evolution. We found that naturally occurring variations at within-membrane residues in the legume Glycine max Cox2 could enable yeast COX2 allotopic expression. We also evidence that directing high doses of allotopically-synthesized Cox2 to mitochondria seems to be counterproductive because the subunit aggregates at the mitochondrial surface. Our findings are relevant for the design of allotopic expression strategies and contribute to the understanding of gene retention in organellar genomes.

DOI: https://doi.org/10.1091/mbc.E18-12-0788

Cells. 2019 Jul 16. pii: E728. [Epub ahead of print]8(7):

Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects.

Giuseppe Paradies, Valeria Paradies, Francesca M Ruggiero, Giuseppe Petrosillo.

In eukaryotic cells, mitochondria are involved in a large array of metabolic and bioenergetic processes that are vital for cell survival. Phospholipids are the main building blocks of mitochondrial membranes. Cardiolipin (CL) is a unique phospholipid which is localized and synthesized in the inner mitochondrial membrane (IMM). It is now widely accepted that CL plays a central role in many reactions and processes involved in mitochondrial function and dynamics. Cardiolipin interacts with and is required for optimal activity of several IMM proteins, including the enzyme complexes of the electron transport chain (ETC) and ATP production and for their organization into supercomplexes. Moreover, CL plays an important role in mitochondrial membrane morphology, stability and dynamics, in mitochondrial biogenesis and protein import, in mitophagy, and in different mitochondrial steps of the apoptotic process. It is conceivable that abnormalities in CL content, composition and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of pathophysiological situations and diseases. In this review, we focus on the role played by CL in mitochondrial function and dynamics in health and diseases and on the potential of pharmacological modulation of CL through several agents in attenuating mitochondrial dysfunction.

Keywords: Cardiolipin; mitochondrial structure-function; pharmacological agents; physiopathology

DOI: https://doi.org/10.3390/cells8070728

IUCrJ. 2019 Jul 01. 6(Pt 4): 773-780

Cryo-EM structure of Neurospora crassa respiratory complex IV.

Thomas Bausewein, Stephan Nussberger, Werner Kühlbrandt.

In fungi, the mitochondrial respiratory chain complexes (complexes I-IV) are responsible for oxidative phosphorylation, as in higher eukaryotes. Cryo-EM was used to identify a 200 kDa membrane protein from Neurospora crassa in lipid nanodiscs as cytochrome c oxidase (complex IV) and its structure was determined at 5.5 Å resolution. The map closely resembles the cryo-EM structure of complex IV from Saccharomyces cerevisiae. Its ten subunits are conserved in S. cerevisiae and Bos taurus, but other transmembrane subunits are missing. The different structure of the Cox5a subunit is typical for fungal complex IV and may affect the interaction with complex III in a respiratory supercomplex. Additional density was found between the matrix domains of the Cox4 and Cox5a subunits that appears to be specific to N. crassa.

Keywords: 3D reconstruction and image processing; Neurospora crassa; automation; cryo-electron microscopy; cytochrome c oxidase; respiratory complex IV; single-particle cryo-EM; structure determination

DOI: https://doi.org/10.1107/S2052252519007486

Life Sci. 2019 Jul 12. pii: S0024-3205(19)30581-8. [Epub ahead of print] 116655

MitoQ ameliorates testicular damage induced by gamma irradiation in rats: Modulation of mitochondrial apoptosis and steroidogenesis.

Ayman A Ibrahim, Heba M Karam, Esmat A Shaaban, Marwa M Safar, Mohammed F El-Yamany.

AIMS: The deleterious effect of gamma radiation on testicular tissue is a challenging problem in nuclear medicine. This study investigated the potential radioprotective effect of mitoquinol (MitoQ), a mitochondria-targeted antioxidant, against testicular damage induced by gamma irradiation in rats.
MAIN METHODS: Rats were allocated into four groups. The first group served as the control, the second group received MitoQ (2 mg / kg / day; i.p.) for seven days, the third group was exposed to gamma radiation (5 Gy as a single dose) and the last group received MitoQ prior to irradiation. Rats were sacrificed. Then, sperm analyses and the serum testosterone were determined. Moreover, evaluation of mitochondrial oxidative stress parameters (SOD, GSH and GPx) as well as apoptosis indicators (cytochrome-c, Bax, Bcl-2 and caspase-3) was performed. Additionally, analysis of steroidogensis biomarkers (StAR, 3β-HSD and 17β-HSD) and histopathological investigations were carried out.
KEY FINDINGS: MitoQ replenished mitochondrial SOD, GPx and GSH indicating its strong antioxidant effect in addition to its energy preservation manifested by the elevated ATP. MitoQ inhibited the intrinsic apoptosis via diminution of Bax, cytochrome-c and caspase-3 and alleviation of Bcl-2. This antioxidant conferred protection to steroidogenesis as verified by the increase in testosterone and the up-regulation of StAR, 3β-HSD and 17β-HSD expression; these effects might be correlated with its antioxidant/anti-apoptotic potential. Histopathological and sperm analyses corroborated the biochemical findings.
SIGNIFICANCE: This study identifies MitoQ as a novel agent for the management of testicular toxicity induced by gamma irradiation.

Keywords: Gamma radiation; Mitochondria-targeted antioxidant; Mitochondrial apoptosis; Steroidogenesis; Testicular damage

DOI: https://doi.org/10.1016/j.lfs.2019.116655

BMJ Case Rep. 2019 Jul 15. pii: e229668. [Epub ahead of print]12(7):

Mitochondrial respiratory chain complex IV deficiency presenting as neonatal respiratory distress syndrome.

Shrinal Kotecha, Venkatesh Kairamkonda.

A term girl infant delivered following foetal distress presented with early respiratory distress syndrome and lactic acidaemia. She subsequently underwent detailed investigation for primary lactic acidaemia and was identified as homozygous for the c.515A>G,p.(Tyr172Cys) missense variant in the LRPPRC gene. Variants in this gene are known to cause French-Canadian type Leigh syndrome. Both parents were confirmed to be heterozygous for this mutation. This is the first case report of mitochondrial respiratory chain complex IV deficiency presenting as foetal distress and neonatal respiratory distress syndrome.

Keywords: failure to thrive; genetic screening / counselling; genetics; paediatrics; parenteral/enteral feeding

DOI: https://doi.org/10.1136/bcr-2019-229668