bims-cytox1 2017-02-05 papers

Cell Stem Cell. 2017 Jan 25. pii: S1934-5909(16)30469-6. [Epub ahead of print]

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders.

Mitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system.

Keywords: NPCs; calcium; drug discovery; iPSCs; induced pluripotent stem cells; metabolism; mitochondria; mitochondrial disorders; mtDNA mutations; neural progenitors

DOI: https://doi.org/10.1016/j.stem.2016.12.013

Postepy Biochem. 2016 ;62(2): 111-115

[Mitochondrial diseases].

Agnieszka Piotrowska, Elona Jankauskaitė, Ewa Bartnik.

Perturbations of mitochondrial function, which may be caused by mutations in both nuclear and mitochondrial DNA, cause many human diseases. We describe the most frequent mitochondrial diseases, especially those caused by mutations in the nuclear genome, attempts to treat these diseases and possible ways of preventing the transmission of diseases caused by mutations in mitochondrial DNA to successive generations.

Keywords: mitochondrial DNA; mitochondrial diseases

Postepy Biochem. 2016 ;62(2): 94-102

[Mitochondrial proteins - import, export, degradation].

Michał Wasilewski, Katarzyna Chojnacka, Agnieszka Chacińska.

Mitochondria participate in plethora of vital processes in the cell such as energy production, other biochemical pathways and signaling. Over a thousand proteins co-operate to form the proteome of mitochondria. A great majority of mitochondrial precursor proteins are encoded in nuclear DNA and produced in the cytosol. They are targeted to mitochondria and sorted to distinct sub-compartments of mitochondria with the help of specialized translocase machineries. Biogenesis of mitochondrial proteins is completed through precursor maturation events and complex assembly. Mitochondrial homeostasis also requires the presence of clearance mechanisms for degradation of non-functional proteins. In the present review, we summarize the most important aspects of mitochondrial protein biogenesis.

Keywords: mitochondria; protein assembly; protein degradation; protein import; protein processing

Postepy Biochem. 2016 ;62(2): 103-110

[Mitochondrial protein import complexes - a phylogenetic perspective].

Małgorzata Wojtkowska, Hanna Kmita.

The proper functioning of mitochondria and consequently of eukaryotic cells requires protein import into mitochondria. The import proceeds due to the presence of different pathways formed by sophisticated complexes known as the import complexes. The complexes are located in all mitochondrial compartments including the both mitochondrial membranes. Here we collect data concerning the organization of the import complexes and available for representatives of currently distinguished eukaryotic lineages. Despite the lack of many data, the emerging picture indicates at differentiation of the complex organization, particularly observed for the TOM complex. This, in turn, implicates interesting issues for further discussion concerning mitochondria evolution and the knowledge practical application.

Keywords: eukaryotic lineages; import complexes; protein import into mitochondria

Postepy Biochem. 2016 ;62(2): 206-215

[ATP-dependent proteases in the quality control of mitochondrial proteome].

Marta Kołodziejczak, Magdalena Opalińska, Małgorzata Czarna, Hanna Jańska.

Mitochondria play the fundamental role in energy production and integration of many important metabolic and signalling pathways, which makes them essential for the function of a cell. The optimal operation of mitochondria depends on the qualitative and quantitative composition of the organellar proteins - the proteome. To maintain the homeostasis of the mitochondrial proteome, mitochondria developed a protein quality control system, which acts on the molecular, cellular and organellar levels. ATP-dependent proteases constitute a key element of this system. It consists of Lon/PIM1 and ClpXP proteases located in the mitochondrial matrix as well as AAA proteases anchored in the inner mitochondrial membrane. The ATP-dependent proteases degrade misfolded, damaged or not assembled proteins. These enzymes are also involved in complex regulatory mechanisms such as mitochondrial translation, fusion and response to stress. Lack of any of ATP-dependent proteases leads to mitochondrial dysfunction and the development of many major diseases in humans. This work summarizes the current knowledge of the ATP-dependent proteolytic system in mitochondria in different organisms.

Keywords: AAA protease; ClpXP; FTSH; Lon; mitochondrial proteases; protein quality control in mitochondria

Postepy Biochem. 2016 ;62(2): 158-161

[Dialogues between cell nuclei and mitochondria].

Maciej Szewczyk, Piotr P Stępień.

Mitochondria are not only ATP producing organelles, but they play pivotal roles in apoptosis, neurodegeneration, cancer and aging. Mammalian mitochondrial genome is a small DNA molecule of about 16.5 kb, encoding less than 20 polypeptides and a set of ribosomal RNAs and tRNAs. In order to ensure proper cell functioning a continous communication between cell nucleus and mitochondria must be maintained. This review presents novel developments in the field of nucleo-mitochondrial communications. We discuss the import of regulatory cytosolic miRNAs into mitochondria, export of RNA from mitochondria, the existence of novel 3 polypeptides encoded by the mitochondrial genome and the transfer of mitochondrial DNA to nuclear genomes. Mechanisms of these processes and their significance for cellular homeostasis are poorly known and present an important challenge for molecular biology.

Keywords: NUMTs; RNA export from mitochondria; RNA import to mitochondria; mitochondrial polypeptides; non-coding RNA; nucleo-mitochondrial localization

Biochim Biophys Acta. 2017 Jan 26. pii: S0925-4439(17)30035-2. [Epub ahead of print]

Novel mutation in mitochondrial Elongation Factor EF-Tu associated to dysplastic leukoencephalopathy and defective mitochondrial DNA translation.

Michela Di Nottia, Arianna Montanari, Daniela Verrigni, Romina Oliva, Alessandra Torraco, Erika Fernandez-Vizarra, Daria Diodato, Teresa Rizza, Marzia Bianchi, Michela Catteruccia, Massimo Zeviani, Carlo Dionisi-Vici, Silvia Francisci, Enrico Bertini, Rosalba Carrozzo.

The mitochondrial Elongation Factor Tu (EF-Tu), encoded by the TUFM gene, is a highly conserved GTPase, which is part of the mitochondrial protein translation machinery. In its activated form, it indeed delivers the aminoacyl-tRNAs to the A site of the mitochondrial ribosome. We report here on a baby girl with severe infantile macrocystic leukodystrophy with micropolygyria and a combined defect of complexes I and IV in muscle biopsy, caused by a novel mutation identified in TUFM. Using human mutant cells and the yeast model, we demonstrate the pathological role of the novel variant. Moreover, results of a molecular modeling study suggest that the mutant is inactive in mitochondrial polypeptide chain elongation, probably as a consequence of its reduced ability to bind mitochondrial aa-tRNAs. Four patients have so far been described with mutations in TUFM, but, following the first description of the disease in a single patient, we describe similar clinical and neuroradiological features in an additional patient.

Keywords: Leukodystrophy; Mitochondrial Translation; OXPHOS defects; TUFM

DOI: https://doi.org/10.1016/j.bbadis.2017.01.022

BMC Pharmacol Toxicol. 2017 Jan 30. 18(1): 7

5-aminolevulinic acid combined with ferrous ion reduces adiposity and improves glucose tolerance in diet-induced obese mice via enhancing mitochondrial function.

Urara Ota, Takeshi Hara, Hitoshi Nakagawa, Emi Tsuru, Masayuki Tsuda, Atsuko Kamiya, Yasushi Kuroda, Yuya Kitajima, Aya Koda, Masahiro Ishizuka, Hideo Fukuhara, Keiji Inoue, Taro Shuin, Motowo Nakajima, Tohru Tanaka.

BACKGROUND: Mitochondrial dysfunction is associated with obesity and various obesity-associated pathological conditions including glucose intolerance. 5-Aminolevulinic acid (ALA), a precursor of heme metabolites, is a natural amino acid synthesized in the mitochondria, and various types of cytochromes containing heme contribute to aerobic energy metabolism. Thus, ALA might have beneficial effects on the reduction of adiposity and improvement of glucose tolerance through its promotion of heme synthesis. In the present study, we investigated the effects of ALA combined with sodium ferrous citrate (SFC) on obesity and glucose intolerance in diet-induced obese mice.
METHODS: We used 20-weeks-old male C57BL/6J diet-induced obesity (DIO) mice that had been fed high-fat diet from 4th week or wild-type C57BL/6J mice. The DIO mice were orally administered ALA combined with SFC (ALA/SFC) for 6 weeks. At the 4th and 5th week during ALA/SFC administration, mice were fasted for 5 h and overnight, respectively and used for oral glucose tolerance test. After the ALA/SFC administration, the plasma glucose levels, weight of white adipose tissue, and expression levels of mitochondrial oxidative phosphorylation (OXPHOS) complexes were examined. Furthermore, the effects of ALA/SFC on lipid content and glucose uptake were examined in vitro.
RESULTS: Oral administration of ALA/SFC for 6 weeks reduced the body weight by about 10% and the weight of white adipose tissues in these animals. In vitro, ALA/SFC reduced lipid content in mouse 3T3-L1 adipocytes in a dose dependent manner, and enhanced glucose uptake in 3T3-L1 adipocytes by 70-90% and rat L6 myoblasts by 30% at 6 h. Additionally, oral administration of ALA/SFC reduced plasma glucose levels and improved glucose tolerance in DIO mice. Furthermore, ALA/SFC enhanced the expression of OXPHOS complexes III, IV, and V by 40-70% in white adipose tissues of DIO mice, improving mitochondrial function.
CONCLUSIONS: Our findings indicate that ALA/SFC is effective in the reduction of adiposity and improvement of glucose tolerance, and that the induction of mitochondrial OXPHOS complex III, IV, and V by ALA/SFC might be an essential component of the molecular mechanisms underlying these effects. ALA/SFC might be a useful supplement for obesity and obesity-related metabolic disease such as type 2 diabetes mellitus.

Keywords: 5-aminolevulinic acid; Diet-induced obese mice; Glucose tolerance; Glucose uptake; Mitochondrial oxidative phosphorylation complex; Obesity; White adipose tissue

DOI: https://doi.org/10.1186/s40360-016-0108-3