bims-cytox1 2019-07-07 papers

Issue of 2019–07–07
four papers selected by
Gavin McStay, Staffordshire University

Oxid Med Cell Longev. 2019 ;2019 9537504

Mitochondrial Transfer of Wharton's Jelly Mesenchymal Stem Cells Eliminates Mutation Burden and Rescues Mitochondrial Bioenergetics in Rotenone-Stressed MELAS Fibroblasts.

Tsu-Kung Lin, Shang-Der Chen, Yao-Chung Chuang, Min-Yu Lan, Jiin-Haur Chuang, Pei-Wen Wang, Te-Yao Hsu, Feng-Sheng Wang, Meng-Han Tsai, Sheng-Teng Huang, Xiao-Wen Wang, Po-Chin Tsai, Hung-Yu Lin, Chia-Wei Liou.

Wharton's jelly mesenchymal stem cells (WJMSCs) transfer healthy mitochondria to cells harboring a mitochondrial DNA (mtDNA) defect. Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the major subgroups of mitochondrial diseases, caused by the mt.3243A>G point mutation in the mitochondrial tRNALeu(UUR) gene. The specific aim of the study is to investigate whether WJMSCs exert therapeutic effect for mitochondrial dysfunction in cells of MELAS patient through donating healthy mitochondria. We herein demonstrate that WJMSCs transfer healthy mitochondria into rotenone-stressed fibroblasts of a MELAS patient, thereby eliminating mutation burden and rescuing mitochondrial functions. In the coculture system in vitro study, WJMSCs transferred healthy mitochondria to rotenone-stressed MELAS fibroblasts. By inhibiting actin polymerization to block tunneling nanotubes (TNTs), the WJMSC-conducted mitochondrial transfer was abrogated. After mitochondrial transfer, the mt.3243A>G mutation burden of MELAS fibroblasts was reduced to an undetectable level, with long-term retention. Sequencing results confirmed that the transferred mitochondria were donated from WJMSCs. Furthermore, mitochondrial transfer of WJMSCs to MELAS fibroblasts improves mitochondrial functions and cellular performance, including protein translation of respiratory complexes, ROS overexpression, mitochondrial membrane potential, mitochondrial morphology and bioenergetics, cell proliferation, mitochondrion-dependent viability, and apoptotic resistance. This study demonstrates that WJMSCs exert bioenergetic therapeutic effects through mitochondrial transfer. This finding paves the way for the development of innovative treatments for MELAS and other mitochondrial diseases.

DOI: https://doi.org/10.1155/2019/9537504

Hum Mol Genet. 2019 Jul 05. pii: ddz160. [Epub ahead of print]

Deregulating mitochondrial metabolite and ion transport has beneficial effects in yeast and human cellular models for NARP syndrome.

Xin Su, Malgorzata Rak, Emmanuel Tetaud, François Godard, Elodie Sardin, Marine Bouhier, Kewin Gombeau, Derek Caetano-Anollés, Bénédicte Salin, Huimei Chen, Jean-Paul di Rago, Déborah Tribouillard-Tanvier.

The m.8993T>G mutation of the mitochondrial MT-ATP6 gene has been associated with numerous cases of neuropathy, ataxia, and retinitis pigmentosa (NARP) and maternally inherited Leigh Syndrome (MILS), which are diseases known to result from abnormalities affecting mitochondrial energy production. We previously reported that an equivalent point mutation severely compromised proton transport through the ATP synthase membrane domain (FO) in Saccharomyces cerevisiae, and reduced the content of cytochrome c oxidase (Complex IV or COX) by 80%. Herein, we report that overexpression of mitochondrial oxodicarboxylate carrier (Odc1p) considerably increases Complex IV abundance and TCA-mediated substrate-level phosphorylation of ADP, coupled to conversion of α-ketoglutarate into succinate in m.8993T>G yeast. Consistently in m.8993T>G yeast cells, the RTG signaling pathway was found to be strongly induced in order to preserve α-ketoglutarate production; when Odc1p was overexpressed, this stress pathway returned to an almost basal activity. Similar beneficial effects were induced by a partial uncoupling of the mitochondrial membrane with the proton ionophore, CCCP. This chemical considerably improved the glutamine-based, respiration-dependent growth of human cytoplasmic hybrid (cybrid) cells that are homoplasmic for the m.8993T>G mutation. These findings shed light on the interdependence between ATP synthase and Complex IV biogenesis, which could lay the groundwork for the creation of nutritional or metabolic interventions for attenuating the effects of mtDNA mutations.

DOI: https://doi.org/10.1093/hmg/ddz160

Nucleic Acids Res. 2019 Jun 28. pii: gkz505. [Epub ahead of print]

Structural insights into dimethylation of 12S rRNA by TFB1M: indispensable role in translation of mitochondrial genes and mitochondrial function.

Xiaodan Liu, Shengqi Shen, Pengzhi Wu, Fudong Li, Xing Liu, Chongyuan Wang, Qingguo Gong, Jihui Wu, Xuebiao Yao, Huafeng Zhang, Yunyu Shi.

Mitochondria are essential molecular machinery for the maintenance of cellular energy supply by the oxidative phosphorylation system (OXPHOS). Mitochondrial transcription factor B1 (TFB1M) is a dimethyltransferase that maintains mitochondrial homeostasis by catalyzing dimethylation of two adjacent adenines located in helix45 (h45) of 12S rRNA. This m62A modification is indispensable for the assembly and maturation of human mitochondrial ribosomes. However, both the mechanism of TFB1M catalysis and the precise function of TFB1M in mitochondrial homeostasis are unknown. Here we report the crystal structures of a ternary complex of human (hs) TFB1M-h45-S-adenosyl-methionine and a binary complex hsTFB1M-h45. The structures revealed a distinct mode of hsTFB1M interaction with its rRNA substrate and with the initial enzymatic state involved in m62A modification. The suppression of hsTFB1M protein level or the overexpression of inactive hsTFB1M mutants resulted in decreased ATP production and reduced expression of components of the mitochondrial OXPHOS without affecting transcription of the corresponding genes and their localization to the mitochondria. Therefore, hsTFB1M regulated the translation of mitochondrial genes rather than their transcription via m62A modification in h45.

DOI: https://doi.org/10.1093/nar/gkz505

Biochim Biophys Acta Bioenerg. 2019 Jun 25. pii: S0005-2728(19)30068-4. [Epub ahead of print]

Mitochondrial respirasome works as a single unit and the cross-talk between complexes I, III2 and IV stimulates NADH dehydrogenase activity.

Meztli Reyes-Galindo, Roselia Suarez, Mercedes Esparza-Perusquía, Jaime de Lira-Sánchez, J Pablo Pardo, Federico Martínez, Oscar Flores-Herrera.

Ustilago maydis is an aerobic basidiomycete that depends on oxidative phosphorylation for its ATP supply, pointing to the mitochondrion as a key player in its energy metabolism. Mitochondrial respiratory complexes I, III2, and IV occur in supramolecular structures named respirasome. In this work, we characterized the subunit composition and the kinetics of NADH:Q oxidoreductase activity of the digitonine-solubilized respirasome (1600 kDa) and the free-complex I (990 kDa). In the presence of 2,6-dimethoxy-1,4-benzoquinone (DBQ) and cytochrome c, both the respirasome NADH:O2 and the NADH:DBQ oxidoreductase activities were inhibited by rotenone, antimycin A or cyanide. A value of 2.4 for the NADH oxidized/oxygen reduced ratio was determined for the respirasome activity, while ROS production was less than 0.001% of the oxygen consumption rate. Analysis of the NADH:DBQ oxidoreductase activity showed that respirasome was 3-times more active and showed higher affinity than free-complex I. The results suggest that the contacts between complexes I, III2 and IV in the respirasome increase the catalytic efficiency of complex I and regulate its activity to prevent ROS production.

Keywords: Complex I activity; Mitochondrial supercomplexes; ROS production; Respirasome; Ustilago maydis mitochondria

DOI: https://doi.org/10.1016/j.bbabio.2019.06.017