bims-cytox1 2019-09-08 papers

Issue of 2019–09–08
four papers selected by
Gavin McStay, Staffordshire University

Cell Mol Life Sci. 2019 Sep 04.

Insights from Drosophila on mitochondrial complex I.

Shauna-Kay Rhooms, Anjaneyulu Murari, Naga Sri Vidya Goparaju, Maximino Vilanueva, Edward Owusu-Ansah.

NADH:ubiquinone oxidoreductase, more commonly referred to as mitochondrial complex I (CI), is the largest discrete enzyme of the oxidative phosphorylation system (OXPHOS). It is localized to the mitochondrial inner membrane. CI oxidizes NADH generated from the tricarboxylic acid cycle to NAD+, in a series of redox reactions that culminates in the reduction of ubiquinone, and the transport of protons from the matrix across the inner membrane to the intermembrane space. The resulting proton-motive force is consumed by ATP synthase to generate ATP, or harnessed to transport ions, metabolites and proteins into the mitochondrion. CI is also a major source of reactive oxygen species. Accordingly, impaired CI function has been associated with a host of chronic metabolic and degenerative disorders such as diabetes, cardiomyopathy, Parkinson's disease (PD) and Leigh syndrome. Studies on Drosophila have contributed to our understanding of the multiple roles of CI in bioenergetics and organismal physiology. Here, we explore and discuss some of the studies on Drosophila that have informed our understanding of this complex and conclude with some of the open questions about CI that can be resolved by studies on Drosophila.

Keywords: Complex I assembly; Drosophila; Mitochondria; NADH:ubiquinone oxidoreductase; OXPHOS; Supercomplex

DOI: https://doi.org/10.1007/s00018-019-03293-0

Biochem Soc Trans. 2019 Sep 04. pii: BST20190238. [Epub ahead of print]

Evolving mtDNA populations within cells.

Iain G Johnston, Joerg P Burgstaller.

Mitochondrial DNA (mtDNA) encodes vital respiratory machinery. Populations of mtDNA molecules exist in most eukaryotic cells, subject to replication, degradation, mutation, and other population processes. These processes affect the genetic makeup of cellular mtDNA populations, changing cell-to-cell distributions, means, and variances of mutant mtDNA load over time. As mtDNA mutant load has nonlinear effects on cell functionality, and cell functionality has nonlinear effects on tissue performance, these statistics of cellular mtDNA populations play vital roles in health, disease, and inheritance. This mini review will describe some of the better-known ways in which these populations change over time in different organisms, highlighting the importance of quantitatively understanding both mutant load mean and variance. Due to length constraints, we cannot attempt to be comprehensive but hope to provide useful links to some of the many excellent studies on these topics.

Keywords: heteroplasmy; mitochondria; mtDNA

DOI: https://doi.org/10.1042/BST20190238

Neuromuscul Disord. 2019 Aug 21. pii: S0960-8966(19)31081-8. [Epub ahead of print]

A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy.

Debby M E I Hellebrekers, Emma L Blakely, Alexandra T M Hendrickx, Steven A Hardy, Sila Hopton, Gavin Falkous, Irenaeus F M de Coo, Hubert J M Smeets, Nadine M E van der Beek, Robert W Taylor.

We report a novel mitochondrial m.4414T>C variant in the mt-tRNAMet (MT-TM) gene in an adult patient with chronic progressive external ophthalmoplegia and myopathy whose muscle biopsy revealed focal cytochrome c oxidase (COX)-deficient and ragged red fibres. The m.4414T>C variant occurs at a strongly evolutionary conserved sequence position, disturbing a canonical base pair and disrupting the secondary and tertiary structure of the mt-tRNAMet. Definitive evidence of pathogenicity is provided by clear segregation of m.4414T>C mutant levels with COX deficiency in single muscle fibres. Interestingly, the variant is present in skeletal muscle at relatively low levels (30%) and undetectable in accessible, non-muscle tissues from the patient and her asymptomatic brother, emphasizing the continuing requirement for a diagnostic muscle biopsy as the preferred tissue for mtDNA genetic investigations of mt-tRNA variants leading to mitochondrial myopathy.

Keywords: Chronic progressive external ophthalmoplegia; MTTM; Mitochondrial disease; Myopathy; m.4414T>C; mtDNA variant

DOI: https://doi.org/10.1016/j.nmd.2019.08.005

FASEB J. 2019 Sep 05. fj201901331R

Mettl17, a regulator of mitochondrial ribosomal RNA modifications, is required for the translation of mitochondrial coding genes.

Zhennan Shi, Siyuan Xu, Shenghui Xing, Ke Yao, Lei Zhang, Luxi Xue, Peng Zhou, Ming Wang, Guoquan Yan, Pengyuan Yang, Jing Liu, Zeping Hu, Fei Lan.

Embryonic stem cells (ESCs) are pluripotent stem cells with the ability to self-renew and to differentiate into any cell types of the 3 germ layers. Recent studies have demonstrated that there is a strong connection between mitochondrial function and pluripotency. Here, we report that methyltransferase like (Mettl) 17, identified from the clustered regularly interspaced short palindromic repeats knockout screen, is required for proper differentiation of mouse embryonic stem cells (mESCs). Mettl17 is located in mitochondria through its N-terminal targeting sequence and specifically interacts with 12S mitochondrial ribosomal RNA (mt-rRNA) as well as small subunits of mitochondrial ribosome (MSSUs). Loss of Mettl17 affects the stability of both 12S mt-rRNA and its associated proteins of MSSUs. We further showed that Mettl17 is an S-adenosyl methionine (SAM)-binding protein and regulates mitochondrial ribosome function in a SAM-binding-dependent manner. Loss of Mettl17 leads to around 70% reduction of m4C840 and 50% reduction of m5C842 of 12S mt-rRNA, revealing the first regulator of the m4C840 and indicating a crosstalk between the 2 nearby modifications. The defects of mitochondrial ribosome caused by deletion of Mettl17 lead to the impaired translation of mitochondrial protein-coding genes, resulting in significant changes in mitochondrial oxidative phosphorylation and cellular metabolome, which are important for mESC pluripotency.-Shi, Z., Xu, S., Xing, S., Yao, K., Zhang, L., Xue, L., Zhou, P., Wang, M., Yan, G., Yang, P., Liu, J., Hu, Z., Lan, F. Mettl17, a regulator of mitochondrial ribosomal RNA modifications, is required for the translation of mitochondrial coding genes.

Keywords: 12S rRNA; oxidative phosphorylation; rRNA modification

DOI: https://doi.org/10.1096/fj.201901331R