bims-mitran 2023-12-10 papers

Issue of 2023–12–10
three papers selected by
Andreas Kohler, Umeå University

Nat Commun. 2023 Dec 02. 14(1): 7991

Structural insights into the role of GTPBP10 in the RNA maturation of the mitoribosome.

Thu Giang Nguyen, Christina Ritter, Eva Kummer.

Mitochondria contain their own genetic information and a dedicated translation system to express it. The mitochondrial ribosome is assembled from mitochondrial-encoded RNA and nuclear-encoded ribosomal proteins. Assembly is coordinated in the mitochondrial matrix by biogenesis factors that transiently associate with the maturing particle. Here, we present a structural snapshot of a large mitoribosomal subunit assembly intermediate containing 7 biogenesis factors including the GTPases GTPBP7 and GTPBP10. Our structure illustrates how GTPBP10 aids the folding of the ribosomal RNA during the biogenesis process, how this process is related to bacterial ribosome biogenesis, and why mitochondria require two biogenesis factors in contrast to only one in bacteria.

DOI: https://doi.org/10.1038/s41467-023-43599-z

EXCLI J. 2023 ;22 1077-1091

Exploring mito-nuclear genetic factors in Leber's hereditary optic neuropathy: insights from comprehensive profiling of unique cases.

Prakash Chermakani, Poigaialwar Gowri, Shanmugam Mahesh Kumar, Periasamy Sundaresan.

Leber's hereditary optic neuropathy (LHON) is a mitochondrial complex I disorder and causes inexorable painless vision loss. Recent studies from India reported that a significant proportion of LHON patients lack primary mitochondrial DNA mutations, suggesting that alternative genetic factors contribute to disease development. Therefore, this study investigated the genetic profile of LHON-affected individuals in order to understand the role of mito-nuclear genetic factors in LHON. A total of thirty probands displaying symptoms consistent with LHON have undergone whole mitochondrial and whole exome sequencing. Interestingly, whole mtDNA sequencing revealed primary mtDNA mutations in 30 % of the probands (n=9), secondary mtDNA mutations in 40 % of the probands (n=12) and no mitochondrial changes in 30 % of individuals (n=9). Further, WES analysis determined pathogenic mutations in 11 different nuclear genes, especially in cases with secondary mtDNA mutations (n=6) or no mtDNA mutations (n=6). These findings provide valuable insight into LHON genetic predisposition, particularly in cases lacking primary mtDNA mutations. See also Figure 1(Fig. 1).

Keywords: arLHON; mito-nuclear genetic factors; mitochondrial complex I disorder; optic atrophy and vision loss; retinoganglion degeneration

DOI: https://doi.org/10.17179/excli2023-6297

ACS Chem Biol. 2023 Dec 06.

CRISPR Screening in Tandem with Targeted mtDNA Damage Reveals WRNIP1 Essentiality.

Tanja Sack, Piriththiv Dhavarasa, Daniel Szames, Siobhan O'Brien, Stephane Angers, Shana O Kelley.

A major impediment to the characterization of mtDNA repair mechanisms in comparison to nuclear DNA repair mechanisms is the difficulty of specifically addressing mitochondrial damage. Using a mitochondria-penetrating peptide, we can deliver DNA-damaging agents directly to mitochondria, bypassing the nuclear compartment. Here, we describe the use of an mtDNA-damaging agent in tandem with CRISPR/Cas9 screening for the genome-wide discovery of factors essential for mtDNA damage response. Using mitochondria-targeted doxorubicin (mtDox), we generate mtDNA double-strand breaks (mtDSBs) specifically in this organelle. Combined with an untargeted doxorubicin (Dox) screen, we identify genes with significantly greater essentiality during mitochondrial versus nuclear DNA damage. We characterize the essentiality of our top hit, WRNIP1─observed here for the first time to respond to mtDNA damage. We further investigate the mitochondrial role of WRNIP1 in innate immune signaling and nuclear genome maintenance, outlining a model that experimentally supports mitochondrial turnover in response to mtDSBs.

DOI: https://doi.org/10.1021/acschembio.3c00620