bims-cytox1 2020-02-09 papers

Issue of 2020‒02‒09
six papers selected by
Gavin McStay
Staffordshire University

J Intern Med. 2020 Feb 03.

Shaping the mitochondrial inner membrane in health and disease.

Lilia Colina-Tenorio, Patrick Horten, Nikolaus Pfanner, Heike Rampelt.

Mitochondria play central roles in cellular energetics, metabolism and signaling. Efficient respiration, mitochondrial quality control, apoptosis, and inheritance of mitochondrial DNA depend on the proper architecture of the mitochondrial membranes and a dynamic remodeling of inner membrane cristae. Defects in mitochondrial architecture can result in severe human diseases affecting predominantly the nervous system and the heart. Inner membrane morphology is generated and maintained in particular by the mitochondrial contact site and cristae organizing system (MICOS), the F1 Fo -ATP synthase, the fusion protein OPA1/Mgm1, and the non-bilayer-forming phospholipids cardiolipin and phosphatidylethanolamine. These protein complexes and phospholipids are embedded in a network of functional interactions. They communicate with each other and additional factors, enabling them to balance different aspects of cristae biogenesis and to dynamically remodel the inner mitochondrial membrane. Genetic alterations disturbing these membrane shaping factors can lead to human pathologies including fatal encephalopathy, dominant optic atrophy, Leigh syndrome, Parkinson's disease, and Barth syndrome.

Keywords: MICOS; cristae membranes; human disease; mitochondria; mitochondriopathies; oxidative phosphorylation

DOI: https://doi.org/10.1111/joim.13031

Cell Mol Life Sci. 2020 Feb 01.

Endosymbiosis before eukaryotes: mitochondrial establishment in protoeukaryotes.

István Zachar, Gergely Boza.

Endosymbiosis and organellogenesis are virtually unknown among prokaryotes. The single presumed example is the endosymbiogenetic origin of mitochondria, which is hidden behind the event horizon of the last eukaryotic common ancestor. While eukaryotes are monophyletic, it is unlikely that during billions of years, there were no other prokaryote-prokaryote endosymbioses as symbiosis is extremely common among prokaryotes, e.g., in biofilms. Therefore, it is even more precarious to draw conclusions about potentially existing (or once existing) prokaryotic endosymbioses based on a single example. It is yet unknown if the bacterial endosymbiont was captured by a prokaryote or by a (proto-)eukaryote, and if the process of internalization was parasitic infection, slow engulfment, or phagocytosis. In this review, we accordingly explore multiple mechanisms and processes that could drive the evolution of unicellular microbial symbioses with a special attention to prokaryote-prokaryote interactions and to the mitochondrion, possibly the single prokaryotic endosymbiosis that turned out to be a major evolutionary transition. We investigate the ecology and evolutionary stability of inter-species microbial interactions based on dependence, physical proximity, cost-benefit budget, and the types of benefits, investments, and controls. We identify challenges that had to be conquered for the mitochondrial host to establish a stable eukaryotic lineage. Any assumption about the initial interaction of the mitochondrial ancestor and its contemporary host based solely on their modern relationship is rather perilous. As a result, we warn against assuming an initial mutually beneficial interaction based on modern mitochondria-host cooperation. This assumption is twice fallacious: (i) endosymbioses are known to evolve from exploitative interactions and (ii) cooperativity does not necessarily lead to stable mutualism. We point out that the lack of evidence so far on the evolution of endosymbiosis from mutual syntrophy supports the idea that mitochondria emerged from an exploitative (parasitic or phagotrophic) interaction rather than from syntrophy.

Keywords: Endosymbiosis; Eukaryogenesis; Mitochondria; Mutualism; Prokaryotes

DOI: https://doi.org/10.1007/s00018-020-03462-6

Mass Spectrom Rev. 2020 Feb 04.

MASS SPECTROMETRY-BASED MITOCHONDRIAL PROTEOMICS IN HUMAN OVARIAN CANCERS.

Na Li, Xianquan Zhan.

The prominent characteristics of mitochondria are highly dynamic and regulatory, which have crucial roles in cell metabolism, biosynthetic, senescence, apoptosis, and signaling pathways. Mitochondrial dysfunction might lead to multiple serious diseases, including cancer. Therefore, identification of mitochondrial proteins in cancer could provide a global view of tumorigenesis and progression. Mass spectrometry-based quantitative mitochondrial proteomics fulfils this task by enabling systems-wide, accurate, and quantitative analysis of mitochondrial protein abundance, and mitochondrial protein posttranslational modifications (PTMs). Multiple quantitative proteomics techniques, including isotope-coded affinity tag, stable isotope labeling with amino acids in cell culture, isobaric tags for relative and absolute quantification, tandem mass tags, and label-free quantification, in combination with different PTM-peptide enrichment methods such as TiO2 enrichment of tryptic phosphopeptides and antibody enrichment of other PTM-peptides, increase flexibility for researchers to study mitochondrial proteomes. This article reviews isolation and purification of mitochondria, quantitative mitochondrial proteomics, quantitative mitochondrial phosphoproteomics, mitochondrial protein-involved signaling pathway networks, mitochondrial phosphoprotein-involved signaling pathway networks, integration of mitochondrial proteomic and phosphoproteomic data with whole tissue proteomic and transcriptomic data and clinical information in ovarian cancers (OC) to in-depth understand its molecular mechanisms, and discover effective mitochondrial biomarkers and therapeutic targets for predictive, preventive, and personalized treatment of OC. This proof-of-principle model about OC mitochondrial proteomics is easily implementable to other cancer types. © 2020 Wiley Periodicals, Inc. Mass Spec Rev.

Keywords: biomarkers; diagnostic targets; individualized patient profiling; mitochondria; molecular network; multiomics; ovarian cancer; patient stratification; quantitative phosphoproteomics; quantitative proteomics; therapeutic targets

DOI: https://doi.org/10.1002/mas.21618

Hum Mol Genet. 2020 Feb 03. pii: ddaa020. [Epub ahead of print]

Mutation m.3395A > G in MT-ND1 leads to variable pathologic manifestations.

Nicolás Gutiérrez Cortés, Claire Pertuiset, Elodie Dumon, Marine Börlin, Barbara Da Costa, Marina Le Guédard, Tanya Stojkovic, Natalie Loundon, Isabelle Rouillon, Yann Nadjar, Thierry Letellier, Laurence Jonard, Sandrine Marlin, Christophe Rocher.

A non-synonymous mtDNA mutation, m.3395A > G, which changes tyrosine in position 30 to cysteine in p.MT-ND1, was found in several patients with a wide range of clinical phenotypes such as deafness, diabetes and cerebellar syndrome but no Leber's hereditary optic neuropathy. Although this mutation has already been described, its pathogenicity has not been demonstrated. Here, it was found isolated for the first time, allowing a study to investigate its pathogenicity. To do so, we constructed cybrid cell lines and carried out a functional study to assess the possible consequences of the mutation on mitochondrial bioenergetics. Results obtained demonstrated that this mutation causes an important dysfunction of the mitochondrial respiratory chain with a decrease of both activity and quantity of complex I due to a diminution of p.MT-ND1 quantity. However, no subcomplexes were found in cybrids carrying the mutation indicating that the quality of the complex I assembly is not affected. Moreover, based on the crystal structure of p.MT-ND1 and the data found in the literature, we propose a hypothesis for the mechanism of the degradation of p.MT-ND1. Our study provides new insights into the pathophysiology of mitochondrial diseases and in particular of MT-ND1 mutations.

DOI: https://doi.org/10.1093/hmg/ddaa020

Mol Aspects Med. 2020 Feb 03. pii: S0098-2997(19)30117-7. [Epub ahead of print] 100842

Mitochondrial functions and rare diseases.

L Dard, W Blanchard, C Hubert, D Lacombe, R Rossignol.

Mitochondria are dynamic cellular organelles responsible for a large variety of biochemical processes as energy transduction, REDOX signaling, the biosynthesis of hormones and vitamins, inflammation or cell death execution. Cell biology studies established that 1158 human genes encode proteins localized to mitochondria, as registered in MITOCARTA. Clinical studies showed that a large number of these mitochondrial proteins can be altered in expression and function through genetic, epigenetic or biochemical mechanisms including the interaction with environmental toxics or iatrogenic medicine. As a result, pathogenic mitochondrial genetic and functional defects participate to the onset and the progression of a growing number of rare diseases. In this review we provide an exhaustive survey of the biochemical, genetic and clinical studies that demonstrated the implication of mitochondrial dysfunction in human rare diseases. We discuss the striking diversity of the symptoms caused by mitochondrial dysfunction and the strategies proposed for mitochondrial therapy, including a survey of ongoing clinical trials.

Keywords: Bioenergetics; Iatrogeny; Mitochondria; REDOX; Rare diseases

DOI: https://doi.org/10.1016/j.mam.2019.100842

Medicine (Baltimore). 2020 Feb;99(6): e18488

Variant m.1555A>G in MT-RNR1 causes hearing loss and multiorgan mitochondrial disorder.

Josef Finsterer.

BACKGROUND: Mitochondrial disorders (MIDs) are usually multisystem disorders, affecting not only a single organ/tissue but also progressively more than one.METHODS: Letter to the Editor.
RESULTS: Though phenotypic manifestations of the m.1555A>G mutation are usually mono-organic, there are indications that short stature, osteoporosis, arterial hypertension, and recurrent headache can be also a manifestation of this variant.MID patients with apparently single organ involvement need to be prospectively investigated for multisystem disease, as multisystem manifestations can be subtle or even subclinical.Concerning the phenotypic expression of the m.1555A>G variant it is crucial to know the heteroplasmy rates in various tissues, as they may strongly contribute to the phenotypic expression of the disease. Maternal transmission can be confirmed by running a basic local alignment search tool.
CONCLUSIONS: The m.1555A>G variant is not only associated with hearing loss but with a number of other multiorgan manifestations. Heteroplasmy rate are required for establishing a genotype/phenotype correlation.

DOI: https://doi.org/10.1097/MD.0000000000018488