bims-cytox1 2019-11-24 papers

Issue of 2019–11–24
four papers selected by
Gavin McStay, Staffordshire University

J Clin Med. 2019 Nov 19. pii: E2020. [Epub ahead of print]8(11):

Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants.

Rocio Rius, Nicole J Van Bergen, Alison G Compton, Lisa G Riley, Maina P Kava, Shanti Balasubramaniam, David J Amor, Miriam Fanjul-Fernandez, Mark J Cowley, Michael C Fahey, Mary K Koenig, Gregory M Enns, Simon Sadedin, Meredith J Wilson, Tiong Y Tan, David R Thorburn, John Christodoulou.

PNPT1 (PNPase-polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic PNPT1 variants cause heterogeneous clinical phenotypes affecting multiple organs without any established genotype-phenotype correlations. Defects in PNPase can cause variable combined respiratory chain complex defects. Recently, it has been suggested that PNPase can lead to activation of an innate immune response. To better understand the clinical and molecular spectrum of patients with bi-allelic PNPT1 variants, we captured detailed clinical and molecular phenotypes of all 17 patients reported in the literature, plus seven new patients, including a 78-year-old male with the longest reported survival. A functional follow-up of genomic sequencing by cDNA studies confirmed a splicing defect in a novel, apparently synonymous, variant. Patient fibroblasts showed an accumulation of mitochondrial unprocessed PNPT1 transcripts, while blood showed an increased interferon response. Our findings suggest that functional analyses of the RNA processing function of PNPase are more sensitive than testing downstream defects in oxidative phosphorylation (OXPHPOS) enzyme activities. This research extends our knowledge of the clinical and functional consequences of bi-allelic pathogenic PNPT1 variants that may guide management and further efforts into understanding the pathophysiological mechanisms for therapeutic development.

Keywords: OXPHOS; PNPT1; PNPase; interferon; mitochondrial; mutation; respiratory chain; splice defect

DOI: https://doi.org/10.3390/jcm8112020

Curr Pharm Des. 2019 Nov 21.

Neurodegenerative diseases associated with mitochondrial DNA mutations.

Olga A Zhunina, Nikita G Yabbarov, Andrey V Grechko, Shaw-Fang Yet, Igor A Sobenin, Alexander N Orekhov.

Mitochondrial dysfunction underlies several human chronic pathologies, including cardiovascular disorders, cancers and neurodegenerative diseases. Impaired mitochondrial function associated with oxidative stress can be a result of both nuclear and mitochondrial DNA (mtDNA) mutations. Neurological disorders associated with mtDNA mutations include mitochondrial encephalomyopathy, chronic progressive external ophthalmoplegia, neurogenic weakness, and Leigh syndrome. Moreover, mtDNA mutations were shown to play a role in the development of Parkinson and Alzheimer's diseases. In this review, the discuss the current knowledge on the distribution and possible roles of mtDNA mutations in the onset and development of various neurodegenerative diseases, with special focus on Parkinson and Alzheimer's diseases.

Keywords: Parkinson Disease; Alzheimer Disease; Neuropathy; Oxidative Stress; Mitochondria; DNA Damage; Reactive Oxygen Species

DOI: https://doi.org/10.2174/1381612825666191122091320

Nat Struct Mol Biol. 2019 Nov 18.

Cryo-EM structure of the mitochondrial protein-import channel TOM complex at near-atomic resolution.

Kyle Tucker, Eunyong Park.

Nearly all mitochondrial proteins are encoded by the nuclear genome and imported into mitochondria after synthesis on cytosolic ribosomes. These precursor proteins are translocated into mitochondria by the TOM complex, a protein-conducting channel in the mitochondrial outer membrane. We have determined high-resolution cryo-EM structures of the core TOM complex from Saccharomyces cerevisiae in dimeric and tetrameric forms. Dimeric TOM consists of two copies each of five proteins arranged in two-fold symmetry: pore-forming β-barrel protein Tom40 and four auxiliary α-helical transmembrane proteins. The pore of each Tom40 has an overall negatively charged inner surface attributed to multiple functionally important acidic patches. The tetrameric complex is essentially a dimer of dimeric TOM, which may be capable of forming higher-order oligomers. Our study reveals the detailed molecular organization of the TOM complex and provides new insights about the mechanism of protein translocation into mitochondria.

DOI: https://doi.org/10.1038/s41594-019-0339-2

Mol Biol Cell. 2019 Nov 20. mbcE19080450

Coordinated organization of mitochondrial lamellar cristae and gain of COX function during mitochondrial maturation in Drosophila.

Yi-Fan Jiang, Hsiang-Ling Lin, Li-Jie Wang, Tian Hsu, Chi-Yu Fu.

Mitochondrial cristae contain electron transport chain (ETC) complexes and are distinct from the inner boundary membrane (IBM). While many details regarding the regulation of mitochondrial structure are known, the relationship between cristae structure and function during organelle development is not fully described. Here, we used serial-section tomography to characterize the formation of lamellar cristae in immature mitochondria during a period of dramatic mitochondrial development that occurs after Drosophila emergence as an adult. We found that the formation of lamellar cristae was associated with the gain of COX function, and the COX subunit, COX4, was localized predominantly to organized lamellar cristae. Interestingly, 3D tomography showed some COX-positive lamellar cristae were not connected to IBM. We hypothesize that some lamellar cristae may be organized by a vesicle germination process in the matrix, in addition to invagination of IBM. OXA1 protein, which mediates membrane insertion of COX proteins, was also localized to cristae and reticular structures isolated in the matrix additional to the IBM, suggesting that it may participate in the formation of vesicle germination-derived cristae. Overall, our study elaborates on how cristae morphogenesis and functional maturation are intricately associated. Our data support the vesicle germination and membrane invagination models of cristae formation. [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E19-08-0450