bims-cytox1 2020-08-16 papers

Issue of 2020‒08‒16
two papers selected by
Gavin McStay
Staffordshire University

N Engl J Med. 2020 Aug 12.

Purifying Selection against Pathogenic Mitochondrial DNA in Human T Cells.

Melissa A Walker, Caleb A Lareau, Leif S Ludwig, Amel Karaa, Vijay G Sankaran, Aviv Regev, Vamsi K Mootha.

Many mitochondrial diseases are caused by mutations in mitochondrial DNA (mtDNA). Patients' cells contain a mixture of mutant and nonmutant mtDNA (a phenomenon called heteroplasmy). The proportion of mutant mtDNA varies across patients and among tissues within a patient. We simultaneously assayed single-cell heteroplasmy and cell state in thousands of blood cells obtained from three unrelated patients who had A3243G-associated mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. We observed a broad range of heteroplasmy across all cell types but also found markedly reduced heteroplasmy in T cells, a finding consistent with purifying selection within this lineage. We observed this pattern in six additional patients who had heteroplasmic A3243G without strokelike episodes. (Funded by the Marriott Foundation and others.).

DOI: https://doi.org/10.1056/NEJMoa2001265

Stem Cell Res. 2020 Aug 03. pii: S1873-5061(20)30236-1. [Epub ahead of print]48 101935

Establishment of variant free-iPSC (UOMi003-A) line from patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes.

Glen Lester Sequiera, Cheryl Rockman-Greenberg, Sanjiv Dhingra.

Heteroplasmy in patients affected with Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) offers a chance to harvest specific cells which might have a very low or no mutation load of the mitochondrial DNA. Here we demonstrate establishment of induced pluripotent stem cells (iPSC) cell lines (with normal mitochondrial DNA copies), from unaffected tissues of a male patient with MELAS harbouring m.3243A > G mutations. This platform allowed us to compare specific pathway differences between the cells of the affected tissues of the patients and their isogenic counterparts derived from iPSCs, which do not harbour the mutations.

DOI: https://doi.org/10.1016/j.scr.2020.101935