bims-cytox1 2019-04-28 papers

Issue of 2019–04–28
three papers selected by
Gavin McStay, Staffordshire University

Mitochondrion. 2019 Apr 22. pii: S1567-7249(19)30068-6. [Epub ahead of print]

A novel pathogenic m.4412G>A MT-TM mitochondrial DNA variant associated with childhood-onset seizures, myopathy and bilateral basal ganglia changes.

Albert Lim, Emma L Blakely, Karen Baty, Langping He, Sila Hopton, Gavin Falkous, Kenneth McWilliam, Alison Cozens, Robert McFarland, Robert W Taylor.

Mitochondrial DNA variants in the MT-TM (mt-tRNAMet) gene are rare, typically associated with myopathic phenotypes. We identified a novel MT-TM variant resulting in prolonged seizures with childhood-onset myopathy, retinopathy, short stature and elevated CSF lactate associated with bilateral basal ganglia changes on neuroimaging. Muscle biopsy confirmed multiple respiratory chain deficiencies and focal cytochrome c oxidase (COX) histochemical abnormalities. Next-generation sequencing of the mitochondrial genome revealed a novel m.4412G>A variant at high heteroplasmy levels in muscle that fulfils all accepted criteria for pathogenicity including segregation within single muscle fibres, thus broadening the genotypic and phenotypic landscape of mitochondrial tRNA-related disease.

Keywords: Basal ganglia changes; MTTM; Mitochondrial disease; Myopathy; Seizures; mtDNA variant

DOI: https://doi.org/10.1016/j.mito.2019.04.007

Adv Exp Med Biol. 2019 ;1123 179-194

Mitochondrial Heterogeneity in Stem Cells.

Prajna Paramita Naik, Prakash P Praharaj, Chandra S Bhol, Debasna P Panigrahi, Kewal K Mahapatra, Srimanta Patra, Sarbari Saha, Sujit K Bhutia.

Mitochondria are customarily acknowledged as the powerhouse of the cell by virtue of their indispensable role in cellular energy production. In addition, it plays an important role in pluripotency, differentiation, and reprogramming. This review describes variation in the stem cells and their mitochondrial heterogeneity. The mitochondrial variation can be described in terms of structure, function, and subcellular distribution. The mitochondria cristae development status and their localization patterns determine the oxygen consumption rate and ATP production which is a central controller of stem cell maintenance and differentiation. Generally, stem cells show spherical, immature mitochondria with perinuclear distribution. Such mitochondria are metabolically less energetic and low polarized. Moreover, mostly glycolytic energy production is found in pluripotent stem cells with a variation in naïve stem cells which perform oxidative phosphorylation (OXPHOS). This article also describes the structural and functional journey of mitochondria during development. Future insight into underlying mechanisms associated with such alternation in mitochondria of stem cells during embryonic stages could uncover mitochondrial adaptability on cellular demands. Moreover, investigating the importance of mitochondria in pluripotency maintenance might unravel the cause of mitochondrial diseases, aging, and regenerative therapies.

Keywords: Embryonic development; Mitochondria; Mitochondrial heterogeneity; Stem cells

DOI: https://doi.org/10.1007/978-3-030-11096-3_11

Mol Cell. 2019 Apr 13. pii: S1097-2765(19)30235-7. [Epub ahead of print]

ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.

Eduardo Balsa, Meghan S Soustek, Ajith Thomas, Sara Cogliati, Carolina García-Poyatos, Elena Martín-García, Mark Jedrychowski, Steve P Gygi, José Antonio Enriquez, Pere Puigserver.

Endoplasmic reticulum (ER) stress and unfolded protein response are energetically challenging under nutrient stress conditions. However, the regulatory mechanisms that control the energetic demand under nutrient and ER stress are largely unknown. Here we show that ER stress and glucose deprivation stimulate mitochondrial bioenergetics and formation of respiratory supercomplexes (SCs) through protein kinase R-like ER kinase (PERK). Genetic ablation or pharmacological inhibition of PERK suppresses nutrient and ER stress-mediated increases in SC levels and reduces oxidative phosphorylation-dependent ATP production. Conversely, PERK activation augments respiratory SCs. The PERK-eIF2α-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. PERK activation is sufficient to rescue bioenergetic defects caused by complex I missense mutations derived from mitochondrial disease patients. These studies have identified an energetic communication between ER and mitochondria, with implications in cell survival and diseases associated with mitochondrial failures.

Keywords: ATF4; ER stress; PERK; hexosamine pathway; mitochondria; mitochondrial cristae; mitochondrial diseases; nutrient stress; protein glycosylation; respiratory chain supercomplexes

DOI: https://doi.org/10.1016/j.molcel.2019.03.031