bims-cytox1 2019-05-12 papers

Issue of 2019–05–12
four papers selected by
Gavin McStay, Staffordshire University

G3 (Bethesda). 2019 May 10. pii: g3.400315.2019. [Epub ahead of print]

Lethal Interaction of Nuclear and Mitochondrial Genotypes in Drosophila melanogaster.

Tiina S Salminen, Giuseppe Cannino, Marcos T Oliveira, Päivi Lillsunde, Howard T Jacobs, Laurie S Kaguni.

Drosophila melanogaster, like most animal species, displays considerable genetic variation in both nuclear and mitochondrial DNA (mtDNA). Here we tested whether any of four natural mtDNA variants was able to modify the effect of the phenotypically mild, nuclear tko25t mutation, affecting mitochondrial protein synthesis. When combined with tko25t , the mtDNA from wild strain KSA2 produced pupal lethality, accompanied by the presence of melanotic nodules in L3 larvae. KSA2 mtDNA, which carries a substitution at a conserved residue of cytochrome b that is predicted to be involved in subunit interactions within respiratory complex III, conferred drastically decreased respiratory capacity and complex III activity in the tko25t but not a wild-type nuclear background. The complex III inhibitor antimycin A was able to phenocopy effects of the tko25t mutation in the KSA2 mtDNA background. This is the first report of a lethal, nuclear-mitochondrial interaction within a metazoan species, representing a paradigm for understanding genetic interactions between nuclear and mitochondrial genotype relevant to human health and disease.

Keywords: cybrid; cytochrome b; melanotic nodules; mtDNA copy number; respiration

DOI: https://doi.org/10.1534/g3.119.400315

Curr Genet. 2019 May 09.

Regulation of the protein entry gate assembly by mitochondrial porin.

Haruka Sakaue, Toshiya Endo.

Mitochondrial biogenesis and functions rely on transport of their resident proteins as well as small molecules/ions across their membranes. The TOM complex functions as a protein entry gate for most mitochondrial proteins and mitochondrial porin facilitates transport of small-molecule metabolites and ions. We recently found a novel role of porin in regulation of the TOM complex assembly, the dynamic exchange between the dimer and trimer, and different substrate specificities of the dimer and trimer. Using distinct assembly forms customized for different client proteins, the TOM complex can handle ~ 1000 different mitochondrial protein for their import into mitochondria.

Keywords: Assembly; Mitochondria; Porin; Protein import; TOM complex; Translocator

DOI: https://doi.org/10.1007/s00294-019-00979-7

Int J Mol Sci. 2019 May 06. pii: E2221. [Epub ahead of print]20(9):

Transcription, Processing, and Decay of Mitochondrial RNA in Health and Disease.

Arianna Barchiesi, Carlo Vascotto.

Although the large majority of mitochondrial proteins are nuclear encoded, for their correct functioning mitochondria require the expression of 13 proteins, two rRNA, and 22 tRNA codified by mitochondrial DNA (mtDNA). Once transcribed, mitochondrial RNA (mtRNA) is processed, mito-ribosomes are assembled, and mtDNA-encoded proteins belonging to the respiratory chain are synthesized. These processes require the coordinated spatio-temporal action of several enzymes, and many different factors are involved in the regulation and control of protein synthesis and in the stability and turnover of mitochondrial RNA. In this review, we describe the essential steps of mitochondrial RNA synthesis, maturation, and degradation, the factors controlling these processes, and how the alteration of these processes is associated with human pathologies.

Keywords: RNA degradation; RNA processing; RNA transcription; mitochondria; mitochondrial diseases

DOI: https://doi.org/10.3390/ijms20092221

J Genet Genomics. 2019 Apr 23. pii: S1673-8527(19)30067-0. [Epub ahead of print]

Human mitochondrial DNA diseases and Drosophila models.

Zhe Chen, Fan Zhang, Hong Xu.

Mutations that disrupt the mitochondrial genome cause a number of human diseases whose phenotypic presentation varies widely among tissues and individuals. This variability owes in part to the unconventional genetics of mitochondrial DNA (mtDNA), which includes polyploidy, maternal inheritance and dependence on nuclear-encoded factors. The recent development of genetic tools for manipulating mitochondrial genome in Drosophila melanogaster renders this powerful model organism an attractive alternative to mammalian systems for understanding mtDNA-related diseases. In this review, we summarize mtDNA genetics and human mtDNA-related diseases. We highlight existing Drosophila models of mtDNA mutations and discuss their potential use in advancing our knowledge of mitochondrial biology and in modeling human mitochondrial disorders. We also discuss the potential and present challenges of gene therapy for the future treatment of mtDNA diseases.

Keywords: Drosophila model; Mitochondrial DNA; mtDNA disease; mtDNA genetics

DOI: https://doi.org/10.1016/j.jgg.2019.03.009