bims-cytox1 2017-05-07 papers

PLoS One. 2017 ;12(4): e0176795

Selective mitochondrial DNA degradation following double-strand breaks.

Amandine Moretton, Frédéric Morel, Bertil Macao, Philippe Lachaume, Layal Ishak, Mathilde Lefebvre, Isabelle Garreau-Balandier, Patrick Vernet, Maria Falkenberg, Géraldine Farge.

Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as reactive oxygen species, chemotherapeutic agents or ionizing radiations. MtDNA encodes for proteins involved in ATP production, and maintenance of genome integrity following DSBs is thus of crucial importance. However, the mechanisms involved in mtDNA maintenance after DSBs remain unknown. In this study, we investigated the consequences of the production of mtDNA DSBs using a human inducible cell system expressing the restriction enzyme PstI targeted to mitochondria. Using this system, we could not find any support for DSB repair of mtDNA. Instead we observed a loss of the damaged mtDNA molecules and a severe decrease in mtDNA content. We demonstrate that none of the known mitochondrial nucleases are involved in the mtDNA degradation and that the DNA loss is not due to autophagy, mitophagy or apoptosis. Our study suggests that a still uncharacterized pathway for the targeted degradation of damaged mtDNA in a mitophagy/autophagy-independent manner is present in mitochondria, and might provide the main mechanism used by the cells to deal with DSBs.

DOI: https://doi.org/10.1371/journal.pone.0176795

Biophys J. 2017 Apr 25. pii: S0006-3495(17)30375-2. [Epub ahead of print]

Assisted and Unassisted Protein Insertion into Liposomes.

Andreas Kuhn, Maximilian Haase, Sebastian Leptihn.

The insertion of newly synthesized membrane proteins is a well-regulated and fascinating process occurring in every living cell. Several translocases and insertases have been found in prokaryotic and eukaryotic cells, the Sec61 complex and the Get complex in the endoplasmic reticulum and the SecYEG complex and YidC in bacteria and archaea. In mitochondria, TOM and TIM complexes transport nuclear-encoded proteins, whereas the Oxa1 is required for the insertion of mitochondria-encoded membrane proteins. Related to the bacterial YidC and the mitochondrial Oxa1 are the Alb3 and Alb4 proteins in chloroplasts. These membrane insertases are comparably simple and can be studied in vitro, after their biochemical purification and reconstitution in artificial lipid bilayers such as liposomes or nanodiscs. Here, we describe the recent progress to study the molecular mechanism of YidC-dependent and unassisted membrane insertion at the single molecule level.

DOI: https://doi.org/10.1016/j.bpj.2017.03.027

PLoS One. 2017 ;12(4): e0176756

Idiosyncratic recognition of UUG/UUA codons by modified nucleoside 5-taurinomethyluridine, τm5U present at 'wobble' position in anticodon loop of tRNALeu: A molecular modeling approach.

Asmita S Kamble, Prayagraj M Fandilolu, Susmit B Sambhare, Kailas D Sonawane.

Lack of naturally occurring modified nucleoside 5-taurinomethyluridine (τm5U) at the 'wobble' 34th position in tRNALeu causes mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). The τm5U34 specifically recognizes UUG and UUA codons. Structural consequences of τm5U34 to read cognate codons have not been studied so far in detail at the atomic level. Hence, 50ns multiple molecular dynamics (MD) simulations of various anticodon stem loop (ASL) models of tRNALeu in presence and absence of τm5U34 along with UUG and UUA codons were performed to explore the dynamic behaviour of τm5U34 during codon recognition process. The MD simulation results revealed that τm5U34 recognizes G/A ending codons by 'wobble' as well as a novel 'single' hydrogen bonding interactions. RMSD and RMSF values indicate the comparative stability of the ASL models containing τm5U34 modification over the other models, lacking τm5U34. Another MD simulation study of 55S mammalian mitochondrial rRNA with tRNALeu showed crucial interactions between the A-site residues, A918, A919, G256 and codon-anticodon bases. Thus, these results could improve our understanding about the decoding efficiency of human mt tRNALeu with τm5U34 to recognize UUG and UUA codons.

DOI: https://doi.org/10.1371/journal.pone.0176756

Fetal Pediatr Pathol. 2017 Apr 28. 1-2

Renal Tubular Mitochondrial Abnormalities in Complex II/III Respiratory Chain Deficiency.

Joel France, Isa Ashoor, Randall Craver.

Defects in the respiratory chain may present with a wide spectrum of clinical signs and symptoms. In this "Images in Pathology" discussion we correlate the clinical, histologic, and ultrastructural findings in a 12-year-old male with a complex II/III respiratory chain deficiency and kidney dysfunction.

Keywords: Mitochondria; electron microscopy; fanconi syndrome; renal tubulopathy; respiratory chain; ultrastructure

DOI: https://doi.org/10.1080/15513815.2017.1313916

Biochim Biophys Acta. 2017 Apr 25. pii: S0167-4889(17)30108-8. [Epub ahead of print]1864(7): 1285-1294

The antimalarial drug artemisinin induces an additional, Sod1-supressible anti-mitochondrial action in yeast.

Chen Sun, Bing Zhou.

The molecular action of artemisinins (ARTs) is not well understood. To determine the molecular and cellular basis that might underlie their differential effects observed in anti-malarial and anti-cancer studies, we utilized the yeast Saccharomyces cerevisiae to examine their toxicity profiles and properties. Previously we reported that while both low levels (2-8μM) of artemisinin (ART) and dihydroartemisinin (DHA) partly depolarize the mitochondrial membranes, inhibiting yeast growth on non-fermentable media, only DHA at moderate levels (such as 40μM) potently represses yeast growth on fermentable media via a heme-mediated pathway. Here we show that the lack of toxicity of ART even at high levels (200-400μM) on fermentable medium is due to the presence of Sod1. While we expected this normally Sod1-supressed action to be heme-mediated like DHA, surprisingly, this toxicity of ART is due to further depolarization of the mitochondrial membrane. We also found that for DHA, the Sod1-suppressible anti-mitochondrial action is hidden by its heme-mediated cytotoxicity, and becomes readily noticeable only when the heme-mediated action is compromised and Sod1 is inactivated. Based on these findings, we propose that depending on the cell type and particular compound, ARTs work via one or more of the three types of activities: a Sod1-independent, partial mitochondria-depolarizing action; a Sod1-suppressible, more severe mitochondria-depolarizing action; and a heme-mediated general cytotoxicity. These action properties may underlie the disparities seen in the efficacy and toxicity of various ARTs, and additionally suggest it is important for researchers to clearly detail the particular compound when reporting on the effects of ARTs.

Keywords: Heme; Hypoxia; Mitochondria; Qinghaosu; Superoxide dismutase

DOI: https://doi.org/10.1016/j.bbamcr.2017.04.014

Bioinformatics. 2017 May 01. 33(9): 1399-1401

fastMitoCalc: an ultra-fast program to estimate mitochondrial DNA copy number from whole-genome sequences.

Yong Qian, Thomas J Butler, Krista Opsahl-Ong, Nicholas S Giroux, Carlo Sidore, Ramaiah Nagaraja, Francesco Cucca, Luigi Ferrucci, Gonçalo R Abecasis, David Schlessinger, Jun Ding.

Availability and Implementation: fastMitoCalc is available at https://lgsun.irp.nia.nih.gov/hsgu/software/mitoAnalyzer/index.html.
Contact: jun.ding@nih.gov.
Supplementary information: Supplementary data are available at Bioinformatics online.

DOI: https://doi.org/10.1093/bioinformatics/btw835