bims-cytox1 2018-09-30 papers

Issue of 2018–09–30
two papers selected by
Gavin McStay, Staffordshire University

Biol Chem. 2018 Sep 22. pii: /j/bchm.ahead-of-print/hsz-2018-0164/hsz-2018-0164.xml. [Epub ahead of print]

Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I).

Tomoko Ohnishi, S Tsuyoshi Ohnishi, John C Salerno.

NADH-quinone oxidoreductase (complex I) is the largest and most complicated enzyme complex of the mitochondrial respiratory chain. It is the entry site into the respiratory chain for most of the reducing equivalents generated during metabolism, coupling electron transfer from NADH to quinone to proton translocation, which in turn drives ATP synthesis. Dysfunction of complex I is associated with neurodegenerative diseases such as Parkinson's and Alzheimer's, and it is proposed to be involved in aging. Complex I has one non-covalently bound FMN, eight to 10 iron-sulfur clusters, and protein-associated quinone molecules as electron transport components. Electron paramagnetic resonance (EPR) has previously been the most informative technique, especially in membrane in situ analysis. The structure of complex 1 has now been resolved from a number of species, but the mechanisms by which electron transfer is coupled to transmembrane proton pumping remains unresolved. Ubiquinone-10, the terminal electron acceptor of complex I, is detectable by EPR in its one electron reduced, semiquinone (SQ) state. In the aerobic steady state of respiration the semi-ubiquinone anion has been observed and studied in detail. Two distinct protein-associated fast and slow relaxing, SQ signals have been resolved which were designated SQNf and SQNs. This review covers a five decade personal journey through the field leading to a focus on the unresolved questions of the role of the SQ radicals and their possible part in proton pumping.

Keywords: EPR spectroscopy; NADH dehydrogenase; complex I; proton translocation; quinone radicals; respiratory chain

DOI: https://doi.org/10.1515/hsz-2018-0164

Am J Med Genet A. 2018 Sep 23. e40516

Care4Rare Canada Consortium

PNPT1 is a mitochondrial RNA transport protein that has been linked to two discrete phenotypes, namely isolated sensorineural hearing loss (OMIM 614934) and combined oxidative phosphorylation deficiency (OMIM 614932). The latter has been described in multiple families presenting with complex neurologic manifestations in childhood. We describe adult siblings with biallelic PNPT1 variants identified through WES who presented with isolated severe congenital sensorineural hearing loss (SNHL). In their 40s, they each developed and then followed a nearly identical neurodegenerative course with ataxia, dystonia, and cognitive decline. Now in their 50s and 60s, all have developed the additional features of optic nerve atrophy, spasticity, and incontinence. The natural history of the condition in this family may suggest that the individuals previously reported as having isolated SNHL may be at risk of developing multisystem disease in late adulthood, and that PNPT1-related disorders may constitute a spectrum rather than distinct phenotypes.

Keywords: autosomal recessive; congenital sensorineural hearing loss; mitochondrial disorders; next generation sequencing; rare diseases

DOI: https://doi.org/10.1002/ajmg.a.40516