bims-cytox1 2017-04-30 papers

Issue of 2017‒04‒30
five papers selected by
Gavin McStay
New York Institute of Technology

J Am Heart Assoc. 2017 Apr 21. pii: e004346. [Epub ahead of print]6(4):

Translocase of Inner Membrane 50 Functions as a Novel Protective Regulator of Pathological Cardiac Hypertrophy.

Kai Tang, Yifan Zhao, Hailing Li, Mengyun Zhu, Weiming Li, Weijing Liu, Guofu Zhu, Dachun Xu, Wenhui Peng, Ya-Wei Xu.

BACKGROUND: Translocase of inner membrane 50 (TIM50) is a member of the translocase of inner membrane (TIM) complex in the mitochondria. Previous research has demonstrated the role of TIM50 in the regulation of oxidative stress and cardiac morphology. However, the role of TIM50 in pathological cardiac hypertrophy remains unknown.METHODS AND RESULTS: In the present study we found that the expression of TIM50 was downregulated in hypertrophic hearts. Using genetic loss-of-function animal models, we demonstrated that TIM50 deficiency increased heart and cardiomyocyte size with more severe cardiac fibrosis compared with wild-type littermates. Moreover, we generated cardiomyocyte-specific TIM50 transgenic mice in which the hypertrophic and fibrotic phenotypes were all alleviated. Next, we tested reactive oxygen species generation and the activities of the antioxidant enzymes superoxide dismutase and catalase, and also respiratory chain complexes I, II, and IV, finding that all the activities were regulated by TIM50. Meanwhile, expression of the ASK1-JNK/P38 axis was increased in TIM50-deficient mice, and TIM50 overexpression decreased the activity of the ASK1-JNK/P38 axis. Finally, we treated mice with the antioxidant N-acetyl cysteine to reduce oxidative stress. After N-acetyl cysteine treatment, the deteriorative hypertrophic and fibrotic phenotypes caused by TIM50 deficiency were all remarkably reversed.
CONCLUSIONS: These data indicated that TIM50 could attenuate pathological cardiac hypertrophy primarily by reducing oxidative stress. TIM50 could be a promising target for the prevention and therapy of cardiac hypertrophy and heart failure.

Keywords: TAK1‐JNK/P38; cardiac hypertrophy; heart failure; mitochondrial; oxidative stress; translocase of inner membrane 50

DOI: https://doi.org/10.1161/JAHA.116.004346

Hum Mol Genet. 2017 Apr 18.

Respiratory chain enzyme deficiency induces mitochondrial location of actin-binding Gelsolin to modulate the oligomerization of VDAC complexes and cell survival.

Alberto García-Bartolomé, Ana Peñas, Lorena Marín-Buera, Teresa Lobo-Jarne, Rafael Pérez-Pérez, María Morán, Joaquín Arenas, Miguel A Martín, Cristina Ugalde.

Despite considerable knowledge on the genetic basis of mitochondrial disorders, their pathophysiological consequences remain poorly understood. We previously used 2D-DIGE analyses to define a protein profile characteristic for respiratory chain complex III-deficiency that included a significant overexpression of cytosolic Gelsolin (GSN), a cytoskeletal protein that regulates the severing and capping of the actin filaments. Biochemical and immunofluorescence assays confirmed a specific increase of GSN levels in the mitochondria from patientś fibroblasts and from transmitochondrial cybrids with complex III assembly defects. A similar effect was obtained in control cells upon treatment with antimycin A in a dose-dependent manner, showing that the enzymatic inhibition of complex III is sufficient to promote the mitochondrial localization of GSN. Mitochondrial subfractionation showed the localization of GSN to the mitochondrial outer membrane, where it interacts with the voltage-dependent anion channel protein 1 (VDAC1). In control cells, VDAC1 was present in five stable oligomeric complexes, which showed increased levels and a modified distribution pattern in the complex III-deficient cybrids. Downregulation of GSN expression induced cell death in both cell types, in parallel with the specific accumulation of VDAC1 dimers and the release of mitochondrial cytochrome c into the cytosol, indicating a role for GSN in the oligomerization of VDAC complexes and in the prevention of apoptosis. Our results demonstrate that respiratory chain complex III dysfunction induces the physiological upregulation and mitochondrial location of GSN, probably to promote cell survival responses through the modulation of the oligomeric state of the VDAC complexes.

DOI: https://doi.org/10.1093/hmg/ddx144

Hum Mol Genet. 2017 Apr 17.

A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma.

Triinu Siibak, Paula Clemente, Ana Bratic, Helene Bruhn, Timo E S Kauppila, Bertil Macao, Florian A Schober, Nicole Lesko, Rolf Wibom, Karin Naess, Inger Nennesmo, Anna Wedell, Bradley Peter, Christoph Freyer, Maria Falkenberg, Anna Wredenberg.

Mutations in the mitochondrial DNA polymerase, POLG, are associated with a variety of clinical presentations, ranging from early onset fatal brain disease in Alpers syndrome to chronic progressive external ophthalmoplegia. The majority of mutations are linked with disturbances of mitochondrial DNA (mtDNA) integrity and maintenance. On a molecular level, depending on their location within the enzyme, mutations either lead to mtDNA depletion or the accumulation of multiple mtDNA deletions, and in some cases these molecular changes can be correlated to the clinical presentation. We identified a patient with a dominant p.Y955H mutation in POLG, presenting with a severe, early-onset multi-systemic mitochondrial disease with bilateral sensorineural hearing loss, cataract, myopathy, and liver failure. Using a combination of disease models of Drosophila melanogaster (Dm) and in vitro biochemistry analysis, we compare the molecular consequences of the p.Y955H mutation to the well-documented p.Y955C mutation. We demonstrate that both mutations affect mtDNA replication and display a dominant negative effect, with the p.Y955H allele resulting in a more severe polymerase dysfunction.

DOI: https://doi.org/10.1093/hmg/ddx146

Hum Mol Genet. 2017 Apr 19.

Evidence of nuclei-encoded spliceosome mediating splicing of mitochondrial RNA.

Roberto H Herai, Priscilla D Negraes, Alysson R Muotri.

Mitochondria are thought to have originated as free-living prokaryotes. Mitochondria organelles have small circular genomes with substantial structural (absence of histones and introns) and genetic similarity to bacteria. Contrary to the prevailing concept of intronless mitochondria, here we present evidences that mitochondrial RNA transcripts (mtRNA) are not limited to policystronic molecules, but also processed as nuclei-like transcripts that are differentially spliced and expressed in a cell-type specific manner. The presence of canonical splice sites in the mtRNA introns and of core components of the nuclei-encoded spliceosome machinery within the mitochondrial organelle suggest that nuclei-encoded spliceosome can mediate splicing of mtRNA.

DOI: https://doi.org/10.1093/hmg/ddx142

Virology. 2017 Apr 18. pii: S0042-6822(17)30118-6. [Epub ahead of print]507 96-100

Mitovirus UGA(Trp) codon usage parallels that of host mitochondria.

Max L Nibert.

Mitoviruses replicate in mitochondria of their host fungi. They have small RNA genomes that encompass a single ORF encoding the viral RdRp. Since UGA codons encode Trp in fungal mitochondria, the RdRp ORF of a typical mitovirus includes multiple UGA codons. In some mitoviruses, however, the ORF has no such codons, suggesting that these particular viruses may be under selective pressure to exclude them. In this report, new evidence is presented that host fungi whose mitoviruses have no or few UGA codons are distinctive in also having no or few UGA codons in their core mitochondrial genes. Thus, the relative exclusion of such codons in a subset of mitoviruses appears to reflect most fundamentally that UGA(Trp) is a rare mitochondrial codon in their particular hosts. The fact that UGA(Trp) is a rare mitochondrial codon in many fungi appears not to have been widely discussed to date.

Keywords: Fungus; Mitochondrion; Mitovirus; Mycovirus; Narnaviridae; RNA virus; Rare codon; UGA

DOI: https://doi.org/10.1016/j.virol.2017.04.010