bims-cytox1 2021-04-04 papers

Issue of 2021–04–04
five papers selected by
Gavin McStay, Staffordshire University

Life (Basel). 2021 Mar 15. pii: 242. [Epub ahead of print]11(3):

Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology.

Salvatore Nesci, Fabiana Trombetti, Alessandra Pagliarani, Vittoria Ventrella, Cristina Algieri, Gaia Tioli, Giorgio Lenaz.

Under aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled as super-complexes, allows the F1FO-ATP synthase to make ATP from ADP + Pi. Recently mitochondria emerged not only as cell powerhouses, but also as signaling hubs by way of reactive oxygen species (ROS) production. However, when ROS removal systems and/or OXPHOS constituents are defective, the physiological ROS generation can cause ROS imbalance and oxidative stress, which in turn damages cell components. Moreover, the morphology of mitochondria rules cell fate and the formation of the mitochondrial permeability transition pore in the mtIM, which, most likely with the F1FO-ATP synthase contribution, permeabilizes mitochondria and leads to cell death. As the multiple mitochondrial functions are mutually interconnected, changes in protein composition by mutations or in supercomplex assembly and/or in membrane structures often generate a dysfunctional cascade and lead to life-incompatible diseases or severe syndromes. The known structural/functional changes in mitochondrial proteins and structures, which impact mitochondrial bioenergetics because of an impaired or defective energy transduction system, here reviewed, constitute the main biochemical damage in a variety of genetic and age-related diseases.

Keywords: ATP synthase/hydrolase; ROS; cellular signaling; cristae; mitochondrial dysfunction; mitochondrial permeability transition pore; oxidative phosphorylation; respiratory supercomplexes

DOI: https://doi.org/10.3390/life11030242

J Clin Med. 2021 Mar 17. pii: 1249. [Epub ahead of print]10(6):

Mitochondrial Syndromes Revisited.

Daniele Orsucci, Elena Caldarazzo Ienco, Andrea Rossi, Gabriele Siciliano, Michelangelo Mancuso.

In the last ten years, the knowledge of the genetic basis of mitochondrial diseases has significantly advanced. However, the vast phenotypic variability linked to mitochondrial disorders and the peculiar characteristics of their genetics make mitochondrial disorders a complex group of disorders. Although specific genetic alterations have been associated with some syndromic presentations, the genotype-phenotype relationship in mitochondrial disorders is complex (a single mutation can cause several clinical syndromes, while different genetic alterations can cause similar phenotypes). This review will revisit the most common syndromic pictures of mitochondrial disorders, from a clinical rather than a molecular perspective. We believe that the new phenotype definitions implemented by recent large multicenter studies, and revised here, may contribute to a more homogeneous patient categorization, which will be useful in future studies on natural history and clinical trials.

Keywords: CPEO; Leigh syndrome; MELAS; MERRF; MNGIE; NARP; PEO; leber; mitochondrial myopathy; mtDNA

DOI: https://doi.org/10.3390/jcm10061249

Neurol Sci. 2021 Mar 29.

Leber hereditary optic neuropathy and dystonia overlapping mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes due to m.14459G>A mutation.

Xiaolin Yu, Kunqian Ji, Yan Lin, Xuebi Xu, Wei Wang, Ying Li, Jian-Qiang Lu, Yuying Zhao, Chuanzhu Yan.

OBJECTIVE: To report a Chinese family with combined m.14459G>A mutation and m.6064A>T mutation of which the female proband presenting unique Leber hereditary optic neuropathy and dystonia (LDYT) overlapping mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype.
METHODS: Clinical information of the pedigree was collected. We performed muscle biopsy and whole-length mitochondrial DNA (mtDNA) sequencing on the proband. The activity of respiratory chain complexes in immortalized lymphoblasts was determined.
RESULTS: The current 23-year-old proband suffered from vision decline at age 15 and developed seizures and dystonia with bilateral lesions in precentral gyri at age 18. When she was 21, the lesions in bilateral putamen were found with elevated cerebrospinal fluid lactate. Her mother had optic atrophy; one of her brother died at age 4 with respiratory distress; and the other 8-year-old brother was asymptomatic. Muscle biopsy of the proband was unremarkable. The mtDNA sequencing revealed a heteroplasmic m.14459G>A mutation and a previously unreported m.6064A>T mutation. The respiratory chain complex I activity in the proband's immortalized lymphoblasts was 50% less than the normal control; while there was no statistical difference between the proband and the normal control in the activity of complex IV.
CONCLUSIONS: We presented the first case exhibiting LDYT and MELAS phenotype with m.14459G>A mutation, and the decreased complex I activity contributed to the pathogenicity. Our study expanded the clinical spectrum of m.14459G>A mutation.

Keywords: Dystonia; Leber hereditary optic neuropathy; MELAS; m.14459G>A mutation

DOI: https://doi.org/10.1007/s10072-021-05155-9

Int J Mol Sci. 2021 Mar 09. pii: 2746. [Epub ahead of print]22(5):

Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression.

Dimitri Shcherbakov, Reda Juskeviciene, Adrián Cortés Sanchón, Margarita Brilkova, Hubert Rehrauer, Endre Laczko, Erik C Böttger.

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).

Keywords: aging; brain; metabolome; misreading; mitochondria

DOI: https://doi.org/10.3390/ijms22052746

J Med Genet. 2021 Apr 02. pii: jmedgenet-2020-107383. [Epub ahead of print]

Whole genome and exome sequencing identify NDUFV2 mutations as a new cause of progressive cavitating leukoencephalopathy.

Zhimei Liu, Li Zhang, Changhong Ren, Manting Xu, Shufang Li, Rui Ban, Ye Wu, Ling Chen, Suzhen Sun, Matthias Elstner, Masaru Shimura, Minako Ogawa-Tominaga, Kei Murayama, Tieliu Shi, Holger Prokisch, Fang Fang.

BACKGROUND: Progressive cavitating leukoencephalopathy (PCL) is thought to result from mutations in nuclear genes affecting mitochondrial function and energy metabolism. To date, mutations in two subunits of complex I, NDUFS1 and NDUFV1, have been reported to be related to PCL.
METHODS: Patients underwent clinical examinations, brain MRI, skin biopsy and muscle biopsy. Whole-genome or whole-exome sequencing was performed on the index patients from two unrelated families with PCL. The effects of the mutations were examined through complementation of the NDUFV2 mutation by cDNA expression.
RESULTS: The common clinical features of the patients in this study were recurring episodes of acute or subacute developmental regression that appeared in the first years of life, followed by gradual remissions and prolonged periods of stability. MRI showed leukoencephalopathy with multiple cavities. Three novel NDUFV2 missense mutations were identified in these families. Complex I deficiency was confirmed in affected individuals' fibroblasts and a muscle biopsy. Functional and structural analyses revealed that these mutations affect the structural stability and function of the NDUFV2 protein, indicating that defective NDUFV2 function is responsible for the phenotypes in these individuals.
CONCLUSIONS: Here, we report the clinical presentations, neuroimaging and molecular and functional analyses of novel mutations in NDUFV2 in two sibling pairs of two Chinese families presenting with PCL. We hereby expand the knowledge on the clinical phenotypes associated with mutations in NDUFV2 and the genotypes causative for PCL.

Keywords: central nervous system diseases; diagnosis; genotype; neurodegenerative diseases; phenotype

DOI: https://doi.org/10.1136/jmedgenet-2020-107383