bims-cytox1 2017-07-23 papers

FASEB J. 2017 Jul 14. pii: fj.201700283R. [Epub ahead of print]

TRAP1 ameliorates renal tubulointerstitial fibrosis in mice with unilateral ureteral obstruction by protecting renal tubular epithelial cell mitochondria.

Jun-Feng Chen, Qi-Shun Wu, Yu-Xian Xie, Bo-Lin Si, Ping-Ping Yang, Wen-Yan Wang, Qin Hua, Qing He.

Mitochondrial dysfunction causes renal tubular epithelial cell injury and promotes cell apoptosis and renal tubulointerstitial fibrosis (TIF) progression. TNF receptor-associated protein 1 (TRAP1) is a molecular chaperone protein that is localized in mitochondria. It plays an important role in cell apoptosis; however, its functional mechanism in TIF remains unclear. In this study, we observed the effects of TRAP1 in renal tubular epithelial cell mitochondria in mice with unilateral ureteral obstruction and its function in cell apoptosis and TIF. Results show that TRAP1 could protect the mitochondrial structure in renal tubular epithelial cells; maintain the levels of mitochondrial membrane potential, ATP, and mitochondrial DNA copy number; inhibit reactive oxygen species production; stabilize the expression of the mitochondrial inner membrane protein mitofilin; reduce renal tubular epithelial cell apoptosis; and inhibit TIF. These results provide new theoretical foundations for additional understanding of the antifibrotic mechanism of TRAP1 in the kidney.-Chen, J.-F., Wu, Q.-S., Xie, Y.-X., Si, B.-L., Yang, P.-P., Wang, W.-Y., Hua, Q., He, Q. TRAP1 ameliorates renal tubulointerstitial fibrosis in mice with unilateral ureteral obstruction by protecting renal tubular epithelial cell mitochondria.

Keywords: apoptosis; extracellular matrix; mitochondrial DNA; mitofilin; reactive oxygen species

DOI: https://doi.org/10.1096/fj.201700283R

Cell Signal. 2017 Jul 11. pii: S0898-6568(17)30185-7. [Epub ahead of print]

Hypoxia-induced suppression of c-Myc by HIF-2α in human pulmonary endothelial cells attenuates TFAM expression.

Ali J Zarrabi, Derrick Kao, Dustin T Nguyen, Joseph Loscalzo, Diane E Handy.

The adaptive response to hypoxia is mediated in large part by stabilization of the hypoxia-inducible factors, HIF-1α and HIF-2α. A hallmark of this response is the metabolic shift to decreased oxidative phosphorylation and increased glycolysis. We hypothesized that hypoxic responses would include a suppression of mitochondrial gene expression. We determined the effects of hypoxia on TFAM, a key mitochondrial transcription factor, in normal pulmonary artery endothelial cells. Hypoxia decreased gene expression of TFAM and that of its upstream regulator, the transcriptional co-activator PGC1β. Although HIF-1α and HIF-2α pathways both contributed to hypoxia-mediated PGC1β suppression, TFAM suppression was regulated solely by HIF-2α-dependent mechanisms. We found that HIF-2α suppresses TFAM by decreasing c-Myc expression. In addition, we show a role for c-Jun in this pathway, linking HIF-2α with attenuation of c-Jun activation. Taken together, these findings establish a new link between HIF-2α and MAPK-signaling that mediates the adaptive regulation of mitochondrial gene expression under low oxygen tension.

Keywords: Endothelial cells; Hypoxia inducible factors; TFAM; c-Jun; c-Myc

DOI: https://doi.org/10.1016/j.cellsig.2017.07.008

Cell. 2017 Jul 13. pii: S0092-8674(17)30757-2. [Epub ahead of print]170(2): 298-311.e20

Profiling Ssb-Nascent Chain Interactions Reveals Principles of Hsp70-Assisted Folding.

Kristina Döring, Nabeel Ahmed, Trine Riemer, Harsha Garadi Suresh, Yevhen Vainshtein, Markus Habich, Jan Riemer, Matthias P Mayer, Edward P O'Brien, Günter Kramer, Bernd Bukau.

The yeast Hsp70 chaperone Ssb interacts with ribosomes and nascent polypeptides to assist protein folding. To reveal its working principle, we determined the nascent chain-binding pattern of Ssb at near-residue resolution by in vivo selective ribosome profiling. Ssb associates broadly with cytosolic, nuclear, and hitherto unknown substrate classes of mitochondrial and endoplasmic reticulum (ER) nascent proteins, supporting its general chaperone function. Ssb engages most substrates by multiple binding-release cycles to a degenerate sequence enriched in positively charged and aromatic amino acids. Timely association with this motif upon emergence at the ribosomal tunnel exit requires ribosome-associated complex (RAC) but not nascent polypeptide-associated complex (NAC). Ribosome footprint densities along orfs reveal faster translation at times of Ssb binding, mainly imposed by biases in mRNA secondary structure, codon usage, and Ssb action. Ssb thus employs substrate-tailored dynamic nascent chain associations to coordinate co-translational protein folding, facilitate accelerated translation, and support membrane targeting of organellar proteins.

Keywords: Hsp70; NAC; RAAC; Selective ribosome profiling; Ssb; chaperone; co-translational folding; translation

DOI: https://doi.org/10.1016/j.cell.2017.06.038

J Neurol Sci. 2017 Jul 05. pii: S0022-510X(17)30429-X. [Epub ahead of print]

Striatal necrosis due to the m.14459G>A mutation.

Josef Finsterer, Sinda Zarrouk-Mahjoub.

Keywords: Genotype; Mitochondrial; Muscle biopsy; Myopathy; Phenotype; Pregnancy; mtDNA

DOI: https://doi.org/10.1016/j.jns.2017.07.004