bims-cytox1 2020-11-22 papers

Issue of 2020–11–22
two papers selected by
Gavin McStay, Staffordshire University

J Mol Med (Berl). 2020 Nov 17.

Mitochondrial respiratory supercomplexes in mammalian cells: structural versus functional role.

Sabzali Javadov, Sehwan Jang, Xavier R Chapa-Dubocq, Zaza Khuchua, Amadou Ks Camara.

Mitochondria are recognized as the main source of ATP to meet the energy demands of the cell. ATP production occurs by oxidative phosphorylation when electrons are transported through the electron transport chain (ETC) complexes and develop the proton motive force across the inner mitochondrial membrane that is used for ATP synthesis. Studies since the 1960s have been concentrated on the two models of structural organization of ETC complexes known as "solid-state" and "fluid-state" models. However, advanced new techniques such as blue-native gel electrophoresis, mass spectroscopy, and cryogenic electron microscopy for analysis of macromolecular protein complexes provided new data in favor of the solid-state model. According to this model, individual ETC complexes are assembled into macromolecular structures known as respiratory supercomplexes (SCs). A large number of studies over the last 20 years proposed the potential role of SCs to facilitate substrate channeling, maintain the integrity of individual ETC complexes, reduce electron leakage and production of reactive oxygen species, and prevent excessive and random aggregation of proteins in the inner mitochondrial membrane. However, many other studies have challenged the proposed functional role of SCs. Recently, a third model known as the "plasticity" model was proposed that partly reconciles both "solid-state" and "fluid-state" models. According to the "plasticity" model, respiratory SCs can co-exist with the individual ETC complexes. To date, the physiological role of SCs remains unknown, although several studies using tissue samples of patients or animal/cell models of human diseases revealed an associative link between functional changes and the disintegration of SC assembly. This review summarizes and discusses previous studies on the mechanisms and regulation of SC assembly under physiological and pathological conditions.

Keywords: Electron transport chain complexes; Human diseases; Inner mitochondrial membrane; Mitochondria; Respiratory Supercomplexes

DOI: https://doi.org/10.1007/s00109-020-02004-8

J Med Genet. 2020 Nov 18. pii: jmedgenet-2020-107323. [Epub ahead of print]

MELAS-associated m.5541C>T mutation caused instability of mitochondrial tRNATrp and remarkable mitochondrial dysfunction.

Kunqian Ji, Yan Lin, Xuebi Xu, Wei Wang, Dongdong Wang, Chen Zhang, Wei Li, Yuying Zhao, Chuanzhu Yan.

BACKGROUND: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episode (MELAS) is a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA. The causative mutations of MELAS have drawn much attention, among them, mutations in mitochondrial tRNA genes possessing prominent status. However, the detailed molecular pathogenesis of these tRNA gene mutations remains unclear and there are very few effective therapies available to date.
METHODS: We performed muscle histochemistry, genetic analysis, molecular dynamic stimulation and measurement of oxygen consumption rate and respiratory chain complex activities to demonstrate the molecular pathomechanisms of m.5541C>T mutation. Moreover, we use cybrid cells to investigate the potential of taurine to rescue mitochondrial dysfunction caused by this mutation.
RESULTS: We found a pathogenic m.5541C>T mutation in the tRNATrp gene in a large MELAS family. This mutation first affected the maturation and stability of tRNATrp and impaired mitochondrial respiratory chain complex activities, followed by remarkable mitochondrial dysfunction. Surprisingly, we identified that the supplementation of taurine almost completely restored mitochondrial tRNATrp levels and mitochondrial respiration deficiency at the in vitro cell level.
CONCLUSION: The m.5541C>T mutation disturbed the translation machinery of mitochondrial tRNATrp and taurine supplementation may be a potential treatment for patients with m.5541C>T mutation. Further studies are needed to explore the full potential of taurine supplementation as therapy for patients with this mutation.

Keywords: molecular medicine; neurology; neuromuscular diseases

DOI: https://doi.org/10.1136/jmedgenet-2020-107323