bims-cytox1 2018-12-09 papers

bims-cytox1

Biomed News

on Cytochrome oxidase subunit 1

Issue of 2018‒12‒09
eight papers selected by
Gavin McStay
Staffordshire University

Histopathological liver findings in patients with hepatocerebral mitochondrial depletion syndrome with defined molecular basis.
Mitochondrial Electron Transport Chain Complex Dysfunction in MeCP2 Knock-Down Astrocytes: Protective Effects of Quercetin Hydrate.
Structural Patching Fosters Divergence of Mitochondrial Ribosomes.
Biological and Evolutionary Significance of Terminal Extensions of Mitochondrial Translation Initiation Factor 3.
The Cellular Mitochondrial Genome Landscape in Disease.
Treatment strategies for Leber hereditary optic neuropathy.
Inactivation of Lon protease reveals a link between mitochondrial unfolded protein stress and mitochondrial translation inhibition.
EGCG protects cardiomyocytes against hypoxia-reperfusion injury via inhibiting OMA1 activation.

Pol J Pathol. 2018 ;pii: 34119. [Epub ahead of print]69(3): 292-298

Histopathological liver findings in patients with hepatocerebral mitochondrial depletion syndrome with defined molecular basis.

Maciej Pronicki, Dorota Piekutowska-Abramczuk, Dariusz Rokicki, Katarzyna Iwanicka-Pronicka, Wiesława Grajkowska.

 Mitochondrial DNA depletion consisting of the systemic reduction of mtDNA copy number in cells may have a heterogenous genetic basis, resulting from a pathogenic change in the nuclear genes involved in mtDNA synthesis. The mode of inheritance is autosomal recessive. Severe hepatocerebral disease represents one of many different clinical forms of so-called mitochondrial depletion syndrome (MDS). We present the liver histopathology of 13 children who eventually died in the course of hepatocerebral MDS confirmed molecularly, harbouring mutations of DGUOK, MPV17, and POLG genes. Material comprising eight autopsy and five liver biopsy specimens showed a moderately reproducible pattern of parenchymal damage, which we consider potentially helpful in the differential diagnosis and planning of the diagnostic investigation in families of children who died due to early-onset acute liver failure and encephalopathy.

Keywords: DGUOK; MPV17; POLG1; liver failure; mitochondrial DNA depletion

DOI: https://doi.org/10.5114/pjp.2018.79549
J Mol Neurosci. 2018 Dec 06.

Mitochondrial Electron Transport Chain Complex Dysfunction in MeCP2 Knock-Down Astrocytes: Protective Effects of Quercetin Hydrate.

Arpita Dave, Foram Shukla, Hemendra Wala, Prakash Pillai.

  Astrocytes play the central role in CNS metabolism to support neuronal functions. Mehyl-CpG-binding protein 2 (MeCP2) is the global transcription factor with differential expression in neuronal and non-neuronal cells. MeCP2 mutation and downstream detrimental effects have been reported in astrocytes also in MeCP2-associated neurodevelopmental disorder-Rett syndrome. Several studies have shown mitochondrial impairment linked to ROS production and reduced ATP synthesis in Rett patients and models, but consequences of MeCP2 deficiency on mitochondrial electron transport chain complexes in astrocytes and effect of known antioxidant quercetin aglycone has not yet been reported. The present study aimed to investigate effect of quercetin on mitochondrial functioning in MeCP2-deficient astrocytes. Our data show onefold upregulated Uqcrc1 and Ndufv2 gene expression, subtle change in protein expression, and significantly reduced mitochondrial respiratory chain complex-II and complex-III enzyme activities in MeCP2 knock-down astrocytes. Intracellular calcium robustly increased and mitochondrial membrane potential decreased, while no change in ROS was observed in MeCP2 knock-down astrocytes. Quercetin increased MeCP2 and normalized Uqcrc1 and Ndufv2 gene expression but did not modulate MeCP2 and Ndufv2 proteins expression. Interestingly, quercetin upregulated significantly the mitochondrial respiratory complex-II, complex-III, and complex-IV activities in dose-dependent manner. It also restored intracellular calcium level and mitochondrial membrane potential. In vitro observations suggest the beneficial effect of quercetin in mitochondrial functioning in MeCP2-deficient condition. There are no reports focusing on role of quercetin in mitochondrial function in MeCP2-deficient astrocytes, and these observations serve as preliminary data to evaluate quercetin's effects in vivo.

Keywords:  Astrocytes; Electron transport chain; MeCP2; Mitochondria; Quercetin aglycone

DOI:  https://doi.org/10.1007/s12031-018-1197-9
Mol Biol Evol. 2018 Dec 04.

Structural Patching Fosters Divergence of Mitochondrial Ribosomes.

Anton S Petrov, Elizabeth C Wood, Chad R Bernier, Ashlyn M Norris, Alan Brown, A Amunts.

Mitochondrial ribosomes (mitoribosomes) are essential components of all mitochondria that synthesize proteins encoded by the mitochondrial genome. Unlike other ribosomes, mitoribosomes are highly variable across species. The basis for this diversity is not known. Here, we examine the composition and evolutionary history of mitoribosomes across the phylogenetic tree by combining three-dimensional structural information with a comparative analysis of the secondary structures of mitochondrial rRNAs (mt-rRNAs) and available proteomic data. We generate a map of the acquisition of structural variation and reconstruct the fundamental stages that shaped the evolution of the mitoribosomal large subunit and led to this diversity. Our analysis suggests a critical role for ablation and expansion of rapidly evolving mt-rRNA. These changes cause structural instabilities that are "patched" by the acquisition of pre-existing compensatory elements, thus providing opportunities for rapid evolution. This mechanism underlies the incorporation of mt-tRNA into the central protuberance of the mammalian mitoribosome, and the altered path of the polypeptide exit tunnel of the yeast mitoribosome. We propose that since the toolkits of elements utilized for structural patching differ between mitochondria of different species, it fosters the growing divergence of mitoribosomes.

DOI: https://doi.org/10.1093/molbev/msy221
Int J Mol Sci. 2018 Dec 04. pii: E3861. [Epub ahead of print]19(12):

Biological and Evolutionary Significance of Terminal Extensions of Mitochondrial Translation Initiation Factor 3.

Ksenia Derbikova, Anton Kuzmenko, Sergey Levitskii, Maria Klimontova, Ivan Chicherin, Maria V Baleva, Igor A Krasheninnikov, Piotr Kamenski.

  Protein biosynthesis in mitochondria is organized in a bacterial manner. However, during evolution, mitochondrial translation mechanisms underwent many organelle-specific changes. In particular, almost all mitochondrial translation factors, being orthologous to bacterial proteins, are characterized by some unique elements of primary or secondary structure. In the case of the organellar initiation factor 3 (IF3), these elements are several dozen amino acids long N- and C-terminal extensions. This study focused on the terminal extensions of baker's yeast mitochondrial IF3, Aim23p. By in vivo deletion and complementation analysis, we show that at least one extension is necessary for Aim23p function. At the same time, human mitochondrial IF3 is fully functional in yeast mitochondria even without both terminal extensions. While Escherichia coli IF3 itself is poorly active in yeast mitochondria, adding Aim23p terminal extensions makes the resulting chimeric protein as functional as the cognate factor. Our results show that the terminal extensions of IF3 have evolved as the "adaptors" that accommodate the translation factor of bacterial origin to the evolutionary changed protein biosynthesis system in mitochondria.

Keywords:  initiation; initiation factor; mitochondria; terminal extension; translation

DOI:  https://doi.org/10.3390/ijms19123861
Trends Cell Biol. 2018 Nov 30. pii: S0962-8924(18)30190-9. [Epub ahead of print]

The Cellular Mitochondrial Genome Landscape in Disease.

Anne Hahn, Steven Zuryn.

  Mitochondrial genome (mitochondrial DNA, mtDNA) lesions that unbalance bioenergetic and oxidative outputs are an important cause of human disease. A major impediment in our understanding of the pathophysiology of mitochondrial disorders is the complexity with which mtDNA mutations are spatiotemporally distributed and managed within individual cells, tissues, and organs. Unlike the comparatively static nuclear genome, accumulating evidence highlights the variability, dynamism, and modifiability of the mtDNA nucleotide sequence between individual cells over time. In this review, we summarize and discuss the impact of mtDNA defects on disease within the context of a mosaic and shifting mutational landscape.

Keywords:  ROS; aging; cancer; heteroplasmy; mitochondrial DNA (mtDNA); mitochondrial disease

DOI:  https://doi.org/10.1016/j.tcb.2018.11.004
Curr Opin Neurol. 2018 Nov 30.

Treatment strategies for Leber hereditary optic neuropathy.

Neringa Jurkute, Joshua Harvey, Patrick Yu-Wai-Man.

PURPOSE OF REVIEW: Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder in the population and it carries a poor visual prognosis. In this article, we review the development of treatment strategies for LHON, the evidence base and the areas of unmet clinical need.RECENT FINDINGS: There is accumulating evidence that increasing mitochondrial biogenesis could be an effective strategy for protecting retinal ganglion cells in LHON. A number of clinical trials are currently investigating the efficacy of viral-based gene therapy for patients harbouring the m.11778G>A mtDNA mutation. For female LHON carriers of childbearing age, mitochondrial replacement therapy is being offered to prevent the maternal transmission of pathogenic mtDNA mutations.
SUMMARY: Although disease-modifying treatment options remain limited, a better understanding of the underlying disease mechanisms in LHON is paving the way for complementary neuroprotective and gene therapeutic strategies for this mitochondrial optic nerve disorder.

DOI: https://doi.org/10.1097/WCO.0000000000000646
Cell Death Dis. 2018 Dec 05. 9(12): 1168

Inactivation of Lon protease reveals a link between mitochondrial unfolded protein stress and mitochondrial translation inhibition.

Gautam Pareek, Leo J Pallanck.

The mitochondrial Unfolded Protein Response (UPRmt) pathway confers protection from misfolded and aggregated proteins by activating factors that promote protein folding and degradation. Our recent work on Lon protease, a member of the mitochondrial ATPase Associated with diverse cellular Activities (AAA+) family of mitochondrial resident proteases, suggests that mitochondrial translational inhibition may also be a feature of the UPRmt pathway.

DOI: https://doi.org/10.1038/s41419-018-1213-6
J Cell Sci. 2018 Dec 05. pii: jcs.220871. [Epub ahead of print]

EGCG protects cardiomyocytes against hypoxia-reperfusion injury via inhibiting OMA1 activation.

Jinliang Nan, Cunjin Nan, Jian Ye, Lu Qian, Ya Geng, Dawei Xing, Muhammad Saif Ur Rahman, Mingyuan Huang.

  Mitochondria are important for energy production and cardiomyocytes homeostasis. OMA1, a metalloendopeptidase, initiates the proteolytic process of pro-fusion protein, OPA1, to deteriorate mitochondrial structure and function. In this study, mouse embryonic fibroblasts (MEFs) and neonatal mouse cardiomyocytes (NMCMs) subjected to hypoxia-reperfusion (H/R) and/or H2O2 were used to mimic oxidative stress in the heart following ischemia-reperfusion (I/R). In vitro experiments demonstrated that H/R insult and H2O2 stimulation induced self-cleavage of OMA1 and subsequent conversion of OPA1 from long form to short form, leading to mitochondrial fragmentation, cytochrome c release, and apoptosis. By using Molecular Operating Environment (MOE) to simulate the binding interaction of 2295 phytochemicals against OMA1, epigallocatechin gallate (EGCG) and betanin were selected as candidates of OMA1 inhibitor. We found that EGCG directly interacted with OMA1 and potently inhibited self-cleavage of OMA1, leading to attenuated OPA1 cleavage. This study suggests that OMA1 inhibition induced by EGCG can serve as a potential approach to treat cardiac I/R injury.

Keywords:  EGCG; Ischemia-reperfusion; Mitochondrial dynamics; OMA1; OPA1

DOI:  https://doi.org/10.1242/jcs.220871