bims-cytox1 2019-10-20 papers

Pediatr Int. 2019 Oct 18.

Late-onset Leigh syndrome with m.9176T>C mutation in the mitochondrial ATPase 6 gene.

Kazushi Ichikawa, Yu Tsuyusaki, Hiroko Shimbo, Tomohide Goto.

Keywords: ATPase 6; Leigh syndrome; mitochondrial DNA; ophthalmoplegia; ptosis

Semin Cell Dev Biol. 2019 Oct 11. pii: S1084-9521(19)30021-7. [Epub ahead of print]

Mitochondrial heteroplasmy beyond the oocyte bottleneck.

Jelle van den Ameele, Andy Y Z Li, Hansong Ma, Patrick F Chinnery.

Inheritance of the mitochondrial genome does not follow the rules of conventional Mendelian genetics. The mitochondrial DNA (mtDNA) is present in many copies per cell and is inherited through the maternal germline. In addition, mutations in the mtDNA will give rise to heteroplasmy, the coexistence of different mtDNA variants within a single cell, whose levels can vary considerably between cells, organs or organisms. The inheritance and subsequent accumulation of deleterious variants are the cause of severe progressive mitochondrial disorders and play a role in many other conditions, including aging, cancer and neurodegenerative disorders. Here, we discuss the processes that give rise to cell-to-cell variability in mtDNA composition, focussing on somatic mtDNA segregation and on less conventional sources of heteroplasmy: non-maternal inheritance and mtDNA recombination. Understanding how mtDNA variants and mutations emerge and evolve within an organism is of crucial importance to prevent and cure mitochondrial disease and can potentially impact more common aging-associated conditions.

Keywords: Bottleneck; Heteroplasmy; Mitochondrial genome; Paternal leakage; Recombination; Somatic segregation

DOI: https://doi.org/10.1016/j.semcdb.2019.10.001

Nature. 2019 Oct;574(7778): E8-E11

Reversion after replacement of mitochondrial DNA.

Gavin Hudson, Yuko Takeda, Mary Herbert.

DOI: https://doi.org/10.1038/s41586-019-1623-3

EMBO J. 2019 Oct 16. e103472

Mitochondrial cristae as insulated transformers of metabolic energy.

Michael Schlame.

The mitochondrial inner membrane consists of the inner boundary membrane and invaginations called cristae, which differ in protein composition and likely have distinct functions. In this issue of The EMBO Journal, Wolf et al (2019) report that the cristae carry a higher membrane potential than the intervening boundary membranes. Their data suggest electro-chemical discontinuity among segments of the inner membrane, implying that individual cristae may operate with some degree of independence.

DOI: https://doi.org/10.15252/embj.2019103472

Biol Reprod. 2019 Oct 17. pii: ioz202. [Epub ahead of print]

Deleterious mtDNA Mutations are Common in Mature Oocytes.

Heritable mitochondrial DNA (mtDNA) mutations are common, yet only a few recurring pathogenic mtDNA variants account for the majority of known familial cases in humans. Purifying selection in the female germline is thought to be responsible for the elimination of most harmful mtDNA mutations during oogenesis. Here, we show that deleterious mtDNA mutations are abundant in ovulated mature mouse oocytes and preimplantation embryos recovered from PolG mutator females but not in their live offspring. This implies that purifying selection acts not in the maternal germline per se, but during post-implantation development. We further show that oocyte mtDNA mutations can be captured and stably maintained in embryonic stem cells (ESCs) and then reintroduced into chimeras, thereby allowing examination of the effects of specific mutations on fetal and postnatal development.

Keywords: mitochondria; mtDNA; oocyte

DOI: https://doi.org/10.1093/biolre/ioz202

Handb Exp Pharmacol. 2019 Oct 19.

Current and Emerging Therapies for Mitochondriopathies.

Florian B Lagler.

Mitochondrial diseases are a clinically and genetically heterogeneous group of disorders. The underlying dysfunction of the mitochondrial electron transport chain and oxidative phosphorylation is caused by variants of genes encoding mitochondrial proteins. Despite substantial advances in the understanding of the mechanism of these diseases, there are still no satisfactory therapies available. Therapeutic strategies include the use of antioxidants, inducers of mitochondrial biogenesis, enhancers of electron transfer chain function, energy buffers, amino acids restoring NO production, nucleotide bypass therapy, liver transplantation, and gene therapy. Although there are some promising projects underway, to date satisfactory therapies are missing.

Keywords: Amino acids; Antioxidants; Electron transfer chain; Energy buffers; Gene therapy; Mitochondrial biogenesis; Mitochondriopathies; Nucleotide bypass; Therapies

DOI: https://doi.org/10.1007/164_2019_264