bims-cytox1 2019-08-18 papers

Issue of 2019–08–18
five papers selected by
Gavin McStay, Staffordshire University

Mitochondrion. 2019 Aug 13. pii: S1567-7249(19)30050-9. [Epub ahead of print]

Reversible dimerization of cytochrome c oxidase regulates mitochondrial respiration.

Rabia Ramzan, Annika Rhiel, Petra Weber, Bernhard Kadenbach, Sebastian Vogt.

Almost all energy consumed by higher organisms, either in the form of ATP or heat, is produced in mitochondria by respiration and oxidative phosphorylation through five protein complexes in the inner membrane. High-resolution x-ray analysis of crystallized cytochrome c oxidase (CytOx), the final oxygen-accepting complex of the respiratory chain, isolated by using cholate as detergent, revealed a dimeric structure with 13 subunits in each monomer. In contrast, CytOx isolated with non-ionic detergents appeared to be monomeric. Our data indicate in vivo a continuous transition between CytOx monomers and dimers via reversible phosphorylation. Increased intracellular calcium, as a consequence of stress, dephosphorylates and monomerises CytOx, whereas cAMP rephosphorylates and dimerises it. Only dimeric CytOx exhibits an "allosteric ATP-inhibition" which inhibits respiration at high cellular ATP/ADP-ratios and could prevent oxygen radical formation and the generation of diseases.

DOI: https://doi.org/10.1016/j.mito.2019.08.002

Fetal Pediatr Pathol. 2019 Aug 14. 1-4

Liver Pathology in Mitochondrial Complex I Deficiency from Bi-Allelic Mutations in NDUFS2: A Report of Findings at Autopsy.

Ashlie Rubrecht, William Clapp, Archana Shenoy.

Background: Mitochondriopathies are a heterogeneous group of genetic disorders with a wide array of symptomatology, organ system involvement, and inheritance patterns. Neonatal presentation can be fatal with neuromuscular dysfunction, lactic acidosis and hepatic failure. Historic literature has numerous phenotypic illustrations; however, genotypic correlation is limited. With improved testing methods, genotype-phenotype correlation is now increasingly feasible as demonstrated herein. Case Report: We present liver pathology findings in an infant who expired with a diagnostic suspicion of a mitochondrial disorder. Postmortem hepatocyte hypereosinophilia with microvesicular steatosis associated with ultrastructural findings of mitochondrial hyperplasia supported a mitochondriopathy. Genetic testing eventually confirmed mitochondrial complex I deficiency from bi-allelic mutations in NDUFS2. Conclusions: Morphologic attributes can assist in diagnosis of mitochondriopathies before specific genetic testing results are available. This case also highlights that diagnostic information can be gained from ultrastructural examination of postmortem liver tissue.

Keywords: histology; mitochondrial disease; mitochondriopathy; ultrastructure

DOI: https://doi.org/10.1080/15513815.2019.1651800

Elife. 2019 Aug 12. pii: e47163. [Epub ahead of print]8

Defined neuronal populations drive fatal phenotype in a mouse model of Leigh Syndrome.

Irene Bolea, Alejandro Gella, Elisenda Sanz, Patricia Prada-Dacasa, Fabien Menardy, Angela M Bard, Pablo Machuca-Márquez, Abel Eraso-Pichot, Guillem Mòdol-Caballero, Xavier Navarro, Franck Kalume, Albert Quintana.

Mitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. Furthermore, their molecular identity and their contribution to the disease remains unknown. Here, using a mouse model of LS lacking the mitochondrial complex I subunit Ndufs4, we dissect the critical role of genetically-defined neuronal populations in LS progression. Ndufs4 inactivation in Vglut2-expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, Ndufs4 deletion in GABAergic neurons causes basal ganglia inflammation without motor or respiratory involvement, but accompanied by hypothermia and severe epileptic seizures preceding death. These results provide novel insight in the cell type-specific contribution to the pathology, dissecting the underlying cellular mechanisms of MD.

Keywords: mouse; neuroscience

DOI: https://doi.org/10.7554/eLife.47163

Trends Biochem Sci. 2019 Aug 08. pii: S0968-0004(19)30161-6. [Epub ahead of print]

Emerging Roles for the Mitochondrial ATP Synthase Supercomplexes.

Salvatore Nesci, Alessandra Pagliarani.

As pointed out by Gu et al. (Science 2019) in mammalian mitochondria, the H-shaped tetrameric structure of the ATP synthase, the cell powerhouse, consists of two V-shaped dimers linked by two IF1 in antiparallel arrangement. This supramolecular structure reveals new functional/structural roles of the enzyme complex in mitochondria.

Keywords: ATP synthase; cristae; mitochondria; subunit composition; tetrameric form

DOI: https://doi.org/10.1016/j.tibs.2019.07.002