bims-cytox1 2021-11-21 papers

Issue of 2021–11–21
three papers selected by
Gavin McStay, Staffordshire University

Am J Med Genet A. 2021 Nov 19.

Case report of atypical Leigh syndrome in an adolescent male with novel biallelic variants in NDUFAF5 and review of the natural history of NDUFAF5-related disorders.

Nicole R Legro, Ashutosh Kumar, Ermal Aliu.

NDUFAF5 encodes a Complex I assembly factor which is critical to the modification of a core subunit, NDUFS7, in early Complex I factor assembly. Mutations in NDUFAF5 have been previously shown to cause Complex I deficiency leading to mitochondrial respiratory chain impairment. More than 15 individuals affected by variants in NDUFAF5 have been described; however, there is phenotypic heterogeneity within this cohort. Some individuals display features of classical Leigh syndrome with early onset neurodegeneration whereas others live into early adulthood with progressive neurological deficits. Here, we present a clinical report of a 17-year-old African American individual with compound heterozygous mutations in NDUFAF5. The individual presented with childhood onset bilateral optic atrophy and developed progressive neuromuscular decline with relatively preserved cognition over time.

Keywords: Complex I; Leigh syndrome; NDUFAF5; mitochondrial disease

DOI: https://doi.org/10.1002/ajmg.a.62568

Mol Cell. 2021 Nov 08. pii: S1097-2765(21)00910-2. [Epub ahead of print]

Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs.

Eva Schöller, James Marks, Virginie Marchand, Astrid Bruckmann, Christopher A Powell, Markus Reichold, Christian Daniel Mutti, Katja Dettmer, Regina Feederle, Stefan Hüttelmaier, Mark Helm, Peter Oefner, Michal Minczuk, Yuri Motorin, Markus Hafner, Gunter Meister.

Mitochondria contain a specific translation machinery for the synthesis of mitochondria-encoded respiratory chain components. Mitochondrial tRNAs (mt-tRNAs) are also generated from the mitochondrial DNA and, similar to their cytoplasmic counterparts, are post-transcriptionally modified. Here, we find that the RNA methyltransferase METTL8 is a mitochondrial protein that facilitates 3-methyl-cytidine (m3C) methylation at position C32 of the mt-tRNASer(UCN) and mt-tRNAThr. METTL8 knockout cells show a reduction in respiratory chain activity, whereas overexpression increases activity. In pancreatic cancer, METTL8 levels are high, which correlates with lower patient survival and an enhanced respiratory chain activity. Mitochondrial ribosome profiling uncovered mitoribosome stalling on mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons. Further analysis of the respiratory chain complexes using mass spectrometry revealed reduced incorporation of the mitochondrially encoded proteins ND6 and ND1 into complex I. The well-balanced translation of mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons through METTL8-mediated m3C32 methylation might, therefore, facilitate the optimal composition and function of the mitochondrial respiratory chain.

Keywords: METTL8; RNA modification; m(3)C; mt-tRNA; translation

DOI: https://doi.org/10.1016/j.molcel.2021.10.018

EMBO J. 2021 Nov 17. e109519

Widespread use of unconventional targeting signals in mitochondrial ribosome proteins.

Yury S Bykov, Tamara Flohr, Felix Boos, Naama Zung, Johannes M Herrmann, Maya Schuldiner.

Mitochondrial ribosomes are complex molecular machines indispensable for respiration. Their assembly involves the import of several dozens of mitochondrial ribosomal proteins (MRPs), encoded in the nuclear genome, into the mitochondrial matrix. Proteomic and structural data as well as computational predictions indicate that up to 25% of yeast MRPs do not have a conventional N-terminal mitochondrial targeting signal (MTS). We experimentally characterized a set of 15 yeast MRPs in vivo and found that five use internal MTSs. Further analysis of a conserved model MRP, Mrp17/bS6m, revealed the identity of the internal targeting signal. Similar to conventional MTS-containing proteins, the internal sequence mediates binding to TOM complexes. The entire sequence of Mrp17 contains positive charges mediating translocation. The fact that these sequence properties could not be reliably predicted by standard methods shows that mitochondrial protein targeting is more versatile than expected. We hypothesize that structural constraints imposed by ribosome assembly interfaces may have disfavored N-terminal presequences and driven the evolution of internal targeting signals in MRPs.

Keywords: mitochondria; mitochondrial ribosome; mitochondrial targeting signal; targeting; translocation

DOI: https://doi.org/10.15252/embj.2021109519