bims-cytox1 2020-06-28 papers

Issue of 2020–06–28
five papers selected by
Gavin McStay, Staffordshire University

J Cell Sci. 2020 Jun 23. pii: jcs.240374. [Epub ahead of print]

Cardiolipin is required for membrane docking of mitochondrial ribosomes and protein synthesis.

Richard G Lee, Junjie Gao, Stefan J Siira, Anne-Marie Shearwood, Judith A Ermer, Vinzenz Hofferek, James C Mathews, Minghao Zheng, Gavin E Reid, Oliver Rackham, Aleksandra Filipovska.

The mitochondrial inner membrane contains a unique phospholipid known as cardiolipin (CL), which stabilises the protein complexes embedded in the membrane and supports its overall structure. Recent evidence indicates that the mitochondrial ribosome may associate with the inner membrane to facilitate co-translational insertion of the hydrophobic oxidative phosphorylation (OXPHOS) proteins into the inner membrane. We generated three mutant knockout cell lines for the cardiolipin biosynthesis gene Crls1 to investigate the effects of cardiolipin loss on mitochondrial protein synthesis. Reduced CL levels caused altered mitochondrial morphology and transcriptome-wide changes that were accompanied by reduced uncoordinated mitochondrial translation rates and impaired respiratory supercomplex formation. Aberrant protein synthesis was caused by impaired formation and distribution of mitochondrial ribosomes. Reduction or loss of cardiolipin resulted in divergent mitochondrial and endoplasmic reticulum stress responses. We show that cardiolipin is required to stabilise the interaction of the mitochondrial ribosome with the membrane via its association with OXA1 during active translation. This interaction facilitates insertion of newly synthesised mitochondrial proteins into the inner membrane and stabilises the respiratory supercomplexes.

Keywords: Mitochondrial membranes; Mitochondrial ribosomes; Protein synthesis

DOI: https://doi.org/10.1242/jcs.240374

Ann Clin Transl Neurol. 2020 Jun;7(6): 980-991

Mitochondrial encephalopathy Due to a Novel Pathogenic Mitochondrial tRNAGln m.4349C>T Variant.

Kunqian Ji, Wei Wang, Yan Lin, Xuebi Xu, Fuchen Liu, Dongdong Wang, Yuying Zhao, Chuanzhu Yan.

OBJECTIVE: Mitochondrial diseases are a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA, among which, mutations in mitochondrial tRNA genes possessing prominent status. In most of the cases, however, the detailed molecular pathogenesis of these tRNA gene mutations remains unclear.
METHODS: We performed the clinical emulation, muscle histochemistry, northern blotting analysis of tRNA levels, biochemical measurement of respiratory chain complex activities and mitochondrial respirations in muscle tissue and cybrid cells.
RESULTS: We found a novel m.4349C>T mutation in mitochondrial tRNAGln gene in a patient present with encephalopathy, epilepsy, and deafness. We demonstrated molecular pathomechanisms of this mutation. This mutation firstly disturbed the translation machinery of mitochondrial tRNAGln and impaired mitochondrial respiratory chain complex activities, followed by remarkable mitochondrial dysfunction and ROS production.
INTERPRETATION: This study illustrated the pathogenicity of a novel m.4349C>T mutation and provided a better understanding of the phenotype associated with mutations in mitochondrial tRNAGln gene.

Keywords: m.4349C>T mutation; mitochondrial disease; mitochondrial tRNAGln

DOI: https://doi.org/10.1002/acn3.51069

Trends Mol Med. 2020 Jul;pii: S1471-4914(20)30062-9. [Epub ahead of print]26(7): 698-709

Therapeutic Manipulation of mtDNA Heteroplasmy: A Shifting Perspective.

Christopher B Jackson, Doug M Turnbull, Michal Minczuk, Payam A Gammage.

Mutations of mitochondrial DNA (mtDNA) often underlie mitochondrial disease, one of the most common inherited metabolic disorders. Since the sequencing of the human mitochondrial genome and the discovery of pathogenic mutations in mtDNA more than 30 years ago, a movement towards generating methods for robust manipulation of mtDNA has ensued, although with relatively few advances and some controversy. While developments in the transformation of mammalian mtDNA have stood still for some time, recent demonstrations of programmable nuclease-based technology suggest that clinical manipulation of mtDNA heteroplasmy may be on the horizon for these largely untreatable disorders. Here we review historical and recent developments in mitochondrially targeted nuclease technology and the clinical outlook for treatment of hereditary mitochondrial disease.

Keywords: gene therapy; heteroplasmy; mitoTALEN; mitochondrial disease; mtDNA; mtZFN

DOI: https://doi.org/10.1016/j.molmed.2020.02.006

Emerg Top Life Sci. 2020 Jun 23. pii: ETLS20190196. [Epub ahead of print]

Mitochondrial donation - hope for families with mitochondrial DNA disease.

Lyndsey Craven, Julie L Murphy, Doug M Turnbull.

In 2015, the UK became the first country to approve the use of mitochondrial donation. This novel in vitro fertilisation treatment was developed to prevent transmission of mitochondrial DNA (mtDNA) disease and ultimately give more reproductive choice to women at risk of having severely affected offspring. The policy change was a major advance that surmounted many scientific, legislative and clinical challenges. Further challenges have since been addressed and there is now an NHS clinical service available to families with pathogenic mtDNA mutations that provides reproductive advice and options, and a research study to look at the outcome at 18 months of children born after mitochondrial donation.

Keywords: mitochondrial DNA disease; mitochondrial donation; mtDNA

DOI: https://doi.org/10.1042/ETLS20190196

Plant Physiol. 2020 Jun 22. pii: pp.00136.2020. [Epub ahead of print]

Mitochondrial CLPP2 assists coordination and homeostasis of respiratory complexes.

Jakob Petereit, Owen Duncan, Monika W Murcha, Ricarda Fenske, Emilia Cincu, Jonathan Cahn, Adriana Pruzinska, Aneta Ivanova, Laxmikanth Kollipara, Stefanie Wortelkamp, Albert Sickmann, Jiwon Lee, Ryan Lister, A Harvey Millar, Shaobai Huang.

Protein homeostasis in eukaryotic organelles and their progenitor prokaryotes is regulated by a series of proteases including the caseinolytic protease (CLPP). CLPP has essential roles in chloroplast biogenesis and maintenance, but the significance of the plant mitochondrial CLPP remains unknown and factors that aid coordination of nuclear- and mitochondrial-encoded subunits for complex assembly in mitochondria await discovery. We generated knock-out lines of the single gene for the mitochondrial CLP protease subunit, CLPP2, in Arabidopsis thaliana. Mutants had higher abundance of transcripts from mitochondrial genes encoding OXPHOS protein complexes, whereas transcripts for nuclear genes encoding other subunits of the same complexes showed no change in abundance. By contrast, the protein abundance of specific nuclear-encoded subunits in OXPHOS Complexes I and V increased in CLPP2 knockouts, without accumulation of mitochondrial-encoded counterparts in the same complex. Complexes with subunits mainly or entirely encoded in the nucleus were unaffected. Analysis of protein import and function of Complex I revealed that, while function was retained, protein homeostasis was disrupted, leading to accumulation of soluble subcomplexes of nuclear-encoded subunits. Therefore, CLPP2 contributes to the mitochondrial protein degradation network through supporting coordination and homeostasis of protein complexes encoded across mitochondrial and nuclear genomes.

DOI: https://doi.org/10.1104/pp.20.00136