bims-mitran 2022-12-04 papers

Issue of 2022‒12‒04
three papers selected by
Andreas Kohler

FEMS Microbiol Rev. 2022 Nov 30. pii: fuac047. [Epub ahead of print]

Mitochondrial genome maintenance - the kinetoplast story.

Simona Amodeo, Irina Bregy, Torsten Ochsenreiter.

Mitochondrial DNA replication is an essential process in most eukaryotes. Similar to the diversity in mitochondrial genome size and organization in the different eukaryotic supergroups, there is considerable diversity in the replication process of the mitochondrial DNA. In this review, we summarize the current knowledge of mitochondrial DNA replication and the associated factors in trypanosomes with a focus on Trypanosoma brucei, and provide a new model of minicircle replication for this protozoan parasite. The model assumes the mitochondrial DNA (kinetoplast DNA, kDNA) of T. brucei to be loosely diploid in nature and the replication of the genome to occur at two replication centers at the opposing ends of the kDNA disc (also known as antipodal sites, APS). The new model is consistent with the localization of most replication factors and in contrast to the current model, it does not require the assumption of an unknown sorting and transport complex moving freshly replicated DNA to the antipodal sites. In combination with the previously proposed sexual stages of the parasite in the insect vector, the new model provides a mechanism for maintenance of the mitochondrial genetic diversity.

Keywords: Kinetoplast; Trypanosomes; kDNA; mitochondrial DNA; mitochondrial DNA replication

DOI: https://doi.org/10.1093/femsre/fuac047

Brain Pathol. 2022 Nov 30. e13134

Leigh syndrome is the main clinical characteristic of PTCD3 deficiency.

Gerard Muñoz-Pujol, Juan D Ortigoza-Escobar, Abraham J Paredes-Fuentes, Cristina Jou, Olatz Ugarteburu, Laura Gort, Delia Yubero, Angels García-Cazorla, Mar O'Callaghan, Jaume Campistol, Jordi Muchart, Vicente A Yépez, Mirjana Gusic, Julien Gagneur, Holger Prokisch, Rafael Artuch, Antonia Ribes, Roser Urreizti, Frederic Tort.

Mitochondrial translation defects are a continuously growing group of disorders showing a large variety of clinical symptoms including a wide range of neurological abnormalities. To date, mutations in PTCD3, encoding a component of the mitochondrial ribosome, have only been reported in a single individual with clinical evidence of Leigh syndrome. Here, we describe three additional PTCD3 individuals from two unrelated families, broadening the genetic and phenotypic spectrum of this disorder, and provide definitive evidence that PTCD3 deficiency is associated with Leigh syndrome. The patients presented in the first months of life with psychomotor delay, respiratory insufficiency and feeding difficulties. The neurologic phenotype included dystonia, optic atrophy, nystagmus and tonic-clonic seizures. Brain MRI showed optic nerve atrophy and thalamic changes, consistent with Leigh syndrome. WES and RNA-seq identified compound heterozygous variants in PTCD3 in both families: c.[1453-1G>C];[1918C>G] and c.[710del];[902C>T]. The functional consequences of the identified variants were determined by a comprehensive characterization of the mitochondrial function. PTCD3 protein levels were significantly reduced in patient fibroblasts and, consistent with a mitochondrial translation defect, a severe reduction in the steady state levels of complexes I and IV subunits was detected. Accordingly, the activity of these complexes was also low, and high-resolution respirometry showed a significant decrease in the mitochondrial respiratory capacity. Functional complementation studies demonstrated the pathogenic effect of the identified variants since the expression of wild-type PTCD3 in immortalized fibroblasts restored the steady-state levels of complexes I and IV subunits as well as the mitochondrial respiratory capacity. Additionally, minigene assays demonstrated that three of the identified variants were pathogenic by altering PTCD3 mRNA processing. The fourth variant was a frameshift leading to a truncated protein. In summary, we provide evidence of PTCD3 involvement in human disease confirming that PTCD3 deficiency is definitively associated with Leigh syndrome.

Keywords: Leigh syndrome; PTCD3; mitochondria; mitochondrial disorder; mitochondrial translation

DOI: https://doi.org/10.1111/bpa.13134

Proc Natl Acad Sci U S A. 2022 Dec 06. 119(49): e2122073119

Stochastic survival of the densest and mitochondrial DNA clonal expansion in aging.

Ferdinando Insalata, Hanne Hoitzing, Juvid Aryaman, Nick S Jones.

The expansion of mitochondrial DNA molecules with deletions has been associated with aging, particularly in skeletal muscle fibers; its mechanism has remained unclear for three decades. Previous accounts have assigned a replicative advantage (RA) to mitochondrial DNA containing deletion mutations, but there is also evidence that cells can selectively remove defective mitochondrial DNA. Here we present a spatial model that, without an RA, but instead through a combination of enhanced density for mutants and noise, produces a wave of expanding mutations with speeds consistent with experimental data. A standard model based on RA yields waves that are too fast. We provide a formula that predicts that wave speed drops with copy number, consonant with experimental data. Crucially, our model yields traveling waves of mutants even if mutants are preferentially eliminated. Additionally, we predict that mutant loads observed in single-cell experiments can be produced by de novo mutation rates that are drastically lower than previously thought for neutral models. Given this exemplar of how spatial structure (multiple linked mtDNA populations), noise, and density affect muscle cell aging, we introduce the mechanism of stochastic survival of the densest (SSD), an alternative to RA, that may underpin other evolutionary phenomena.

Keywords: aging; biomathematics; evolution; mitochondria; stochastic

DOI: https://doi.org/10.1073/pnas.2122073119