bims-cytox1 2020-05-10 papers

Issue of 2020–05–10
four papers selected by
Gavin McStay, Staffordshire University

Philos Trans R Soc Lond B Biol Sci. 2020 Jun 22. 375(1801): 20190414

Mitochondrial cross-compartmental signalling to maintain proteostasis and longevity.

Marte Molenaars, Eileen G Daniels, Amber Meurs, Georges E Janssens, Riekelt H Houtkooper.

Lifespan in eukaryotic species can be prolonged by shifting from cellular states favouring growth to those favouring maintenance and stress resistance. For instance, perturbations in mitochondrial oxidative phosphorylation (OXPHOS) can shift cells into this latter state and extend lifespan. Because mitochondria rely on proteins synthesized from nuclear as well as mitochondrial DNA, they need to constantly send and receive messages from other compartments of the cell in order to function properly and maintain homeostasis, and lifespan extension is often dependent on this cross-compartmental signalling. Here, we describe the mechanisms of bi-directional mitochondrial cross-compartmental signalling resulting in proteostasis and longevity. These proteostasis mechanisms are highly context-dependent, governed by the origin and extent of stress. Furthermore, we discuss the translatability of these mechanisms and explore therapeutic developments, such as the antibiotic studies targeting mitochondria or mitochondria-derived peptides as therapies for age-related diseases such as neurodegeneration and cancer. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.

Keywords: longevity; mitochondria; proteostasis; retrograde signalling

DOI: https://doi.org/10.1098/rstb.2019.0414

Cell Rep. 2020 May 05. pii: S2211-1247(20)30556-8. [Epub ahead of print]31(5): 107607

Distinct Roles of Mitochondrial HIGD1A and HIGD2A in Respiratory Complex and Supercomplex Biogenesis.

Alba Timón-Gómez, Joshua Garlich, Rosemary A Stuart, Cristina Ugalde, Antoni Barrientos.

The mitochondrial respiratory chain enzymes are organized as individual complexes and supercomplexes, whose biogenesis remains to be fully understood. To disclose the role of the human Hypoxia Inducible Gene Domain family proteins HIGD1A and HIGD2A in these processes, we generate and characterize HIGD-knockout (KO) cell lines. We show that HIGD2A controls and coordinates the modular assembly of isolated and supercomplexed complex IV (CIV) by acting on the COX3 assembly module. In contrast, HIGD1A regulates CIII and CIII-containing supercomplex biogenesis by supporting the incorporation of UQCRFS1. HIGD1A also clusters with COX4-1 and COX5A CIV subunits and, when overexpressed, suppresses the CIV biogenesis defect of HIGD2A-KO cells. We conclude that HIGD1A and HIGD2A have both independent and overlapping functions in the biogenesis of respiratory complexes and supercomplexes. Our data illuminate the existence of multiple pathways to assemble these structures by dynamic HIGD-mediated CIV biogenesis, potentially to adapt to changing environmental and nutritional conditions.

Keywords: COX7A2L; HIGD1A; HIGD2A; OXPHOS; mitochondrial respiratory chain; respirasomes; supercomplexes

DOI: https://doi.org/10.1016/j.celrep.2020.107607

Sci Rep. 2020 May 05. 10(1): 7511

Validation of a mitochondrial RNA therapeutic strategy using fibroblasts from a Leigh syndrome patient with a mutation in the mitochondrial ND3 gene.

Yuma Yamada, Kana Somiya, Akihiko Miyauchi, Hitoshi Osaka, Hideyoshi Harashima.

We report on the validation of a mitochondrial gene therapeutic strategy using fibroblasts from a Leigh syndrome patient by the mitochondrial delivery of therapeutic mRNA. The treatment involves delivering normal ND3 protein-encoding mRNA as a therapeutic RNA to mitochondria of the fibroblasts from a patient with a T10158C mutation in the mtDNA coding the ND3 protein, a component of the mitochondrial respiratory chain complex I. The treatment involved the use of a liposome-based carrier (a MITO-Porter) for delivering therapeutic RNA to mitochondria via membrane fusion. The results confirmed that the mitochondrial transfection of therapeutic RNA by the MITO-Porter system resulted in a decrease in the levels of mutant RNA in mitochondria of diseased cells based on reverse transcription quantitative PCR. An evaluation of mitochondrial respiratory activity by respirometry also showed that transfection using the MITO-Porter resulted in an increase in maximal mitochondrial respiratory activity in the diseased cells.

DOI: https://doi.org/10.1038/s41598-020-64322-8

Int J Mol Sci. 2020 Apr 30. pii: E3182. [Epub ahead of print]21(9):

Functional Mechanisms of Mitochondrial Respiratory Chain Supercomplex Assembly Factors and Their Involvement in Muscle Quality.

Kotaro Azuma, Kazuhiro Ikeda, Satoshi Inoue.

Impairment of skeletal muscle function causes disabilities in elderly people. Therefore, in an aged society, prevention and treatment of sarcopenia are important for expanding healthy life expectancy. In addition to aging, adipose tissue disfunction and inflammation also contribute to the pathogenesis of sarcopenia by causing the combined state called 'sarcopenic obesity'. Muscle quality as well as muscle mass contributes to muscle strength and physical performance. Mitochondria in the skeletal muscles affect muscle quality by regulating the production of energy and reactive oxygen species. A certain portion of the mitochondrial respiratory chain complexes form a higher-order structure called a "supercomplex", which plays important roles in efficient energy production, stabilization of respiratory chain complex I, and prevention of reactive oxygen species (ROS) generation. Several molecules including phospholipids, proteins, and certain chemicals are known to promote or stabilize mitochondrial respiratory chain supercomplex assembly directly or indirectly. In this article, we review the distinct mechanisms underlying the promotion or stabilization of mitochondrial respiratory chain supercomplex assembly by supercomplex assembly factors. Further, we introduce regulatory pathways of mitochondrial respiratory chain supercomplex assembly and discuss the roles of supercomplex assembly factors and regulatory pathways in skeletal muscles and adipose tissues, believing that this will lead to discovery of potential targets for prevention and treatment of muscle disorders such as sarcopenia.

Keywords: adipose tissue; mitochondria; respiratory chain supercomplex; sarcopenia; skeletal muscle

DOI: https://doi.org/10.3390/ijms21093182