bims-mitran 2022-10-09 papers

Issue of 2022–10–09
four papers selected by
Andreas Kohler, University of Graz

Trends Biochem Sci. 2022 Oct 04. pii: S0968-0004(22)00240-7. [Epub ahead of print]

Making ends meet: a universal driver of large ribosomal subunit biogenesis.

Katherine E Bohnsack, Anthony K Henras, Henrik Nielsen, Markus T Bohnsack.

A common aspect of ribosome assembly, conserved across all domains of life, is the establishment of connections between the 5' and 3' ends of the large subunit (LSU) ribosomal RNA (rRNA) to initiate rRNA domain compaction and subunit assembly. We discuss the diverse mechanisms employed in different organisms to accomplish this important event.

Keywords: RNA folding; RNA helicase; RNA stabilization; circular RNA; ribosome assembly; small nucleolar RNA (snoRNA)

DOI: https://doi.org/10.1016/j.tibs.2022.09.003

Nature. 2022 Oct 05.

Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes.

Wei Wei, Katherine R Schon, Greg Elgar, Andrea Orioli, Melanie Tanguy, Adam Giess, Marc Tischkowitz, Mark J Caulfield, Patrick F Chinnery.

DNA transfer from cytoplasmic organelles to the cell nucleus is a legacy of the endosymbiotic event-the majority of nuclear-mitochondrial segments (NUMTs) are thought to be ancient, preceding human speciation1-3. Here we analyse whole-genome sequences from 66,083 people-including 12,509 people with cancer-and demonstrate the ongoing transfer of mitochondrial DNA into the nucleus, contributing to a complex NUMT landscape. More than 99% of individuals had at least one of 1,637 different NUMTs, with 1 in 8 individuals having an ultra-rare NUMT that is present in less than 0.1% of the population. More than 90% of the extant NUMTs that we evaluated inserted into the nuclear genome after humans diverged from apes. Once embedded, the sequences were no longer under the evolutionary constraint seen within the mitochondrion, and NUMT-specific mutations had a different mutational signature to mitochondrial DNA. De novo NUMTs were observed in the germline once in every 104 births and once in every 103 cancers. NUMTs preferentially involved non-coding mitochondrial DNA, linking transcription and replication to their origin, with nuclear insertion involving multiple mechanisms including double-strand break repair associated with PR domain zinc-finger protein 9 (PRDM9) binding. The frequency of tumour-specific NUMTs differed between cancers, including a probably causal insertion in a myxoid liposarcoma. We found evidence of selection against NUMTs on the basis of size and genomic location, shaping a highly heterogenous and dynamic human NUMT landscape.

DOI: https://doi.org/10.1038/s41586-022-05288-7

Mol Cell. 2022 Sep 20. pii: S1097-2765(22)00899-1. [Epub ahead of print]

No role for nuclear transcription regulators in mammalian mitochondria?

Diana Rubalcava-Gracia, Rodolfo García-Villegas, Nils-Göran Larsson.

Although the mammalian mtDNA transcription machinery is simple and resembles bacteriophage systems, there are many reports that nuclear transcription regulators, as exemplified by MEF2D, MOF, PGC-1α, and hormone receptors, are imported into mammalian mitochondria and directly interact with the mtDNA transcription machinery. However, the supporting experimental evidence for this concept is open to alternate interpretations, and a main issue is the difficulty in distinguishing indirect regulation of mtDNA transcription, caused by altered nuclear gene expression, from direct intramitochondrial effects. We provide a critical discussion and experimental guidelines to stringently assess roles of intramitochondrial factors implicated in direct regulation of mammalian mtDNA transcription.

DOI: https://doi.org/10.1016/j.molcel.2022.09.010

Elife. 2022 Oct 06. pii: e80396. [Epub ahead of print]11

Independent regulation of mitochondrial DNA quantity and quality in Caenorhabditis elegans primordial germ cells.

Aaron Z A Schwartz, Nikita Tsyba, Yusuff Abdu, Maulik R Patel, Jeremy Nance.

Mitochondria harbor an independent genome, called mitochondrial DNA (mtDNA), which contains essential metabolic genes. Although mtDNA mutations occur at high frequency, they are inherited infrequently, indicating that germline mechanisms limit their accumulation. To determine how germline mtDNA is regulated, we examined the control of mtDNA quantity and quality in C. elegans primordial germ cells (PGCs). We show that PGCs combine strategies to generate a low point in mtDNA number by segregating mitochondria into lobe-like protrusions that are cannibalized by adjacent cells, and by concurrently eliminating mitochondria through autophagy, reducing overall mtDNA content twofold. As PGCs exit quiescence and divide, mtDNAs replicate to maintain a set point of ~200 mtDNAs per germline stem cell. Whereas cannibalism and autophagy eliminate mtDNAs stochastically, we show that the kinase PTEN-induced kinase 1 (PINK1), operating independently of Parkin and autophagy, preferentially reduces the fraction of mutant mtDNAs. Thus, PGCs employ parallel mechanisms to control both the quantity and quality of the founding population of germline mtDNAs.

Keywords: C. elegans; PINK1; autophagy; bottleneck; cell biology; developmental biology; mitochondrial DNA; primordial germ cells; purifying selection

DOI: https://doi.org/10.7554/eLife.80396