bims-cytox1 2019-03-24 papers

Issue of 2019–03–24
four papers selected by
Gavin McStay, Staffordshire University

EMBO Mol Med. 2019 Mar 18. pii: e9561. [Epub ahead of print]

Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.

Karthik Mohanraj, Michal Wasilewski, Cristiane Benincá, Dominik Cysewski, Jaroslaw Poznanski, Paulina Sakowska, Zaneta Bugajska, Markus Deckers, Sven Dennerlein, Erika Fernandez-Vizarra, Peter Rehling, Michal Dadlez, Massimo Zeviani, Agnieszka Chacinska.

Nuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space (IMS) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein cytochrome c oxidase assembly factor 7 (COA7), or RESpiratory chain Assembly 1 (RESA1) factor that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that COA7 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS We also found that pathogenic mutant versions of COA7 are imported slower than the wild-type protein, and mislocalized proteins are degraded in the cytosol by the proteasome. Interestingly, proteasome inhibition rescued both the mitochondrial localization of COA7 and complex IV activity in patient-derived fibroblasts. We propose proteasome inhibition as a novel therapeutic approach for a broad range of mitochondrial pathologies associated with the decreased levels of mitochondrial proteins.

Keywords: COA7/RESA1; mitochondrial disease; proteasome; protein degradation; protein import

DOI: https://doi.org/10.15252/emmm.201809561

Nat Cell Biol. 2019 Mar 18.

Mitochondrial protein-induced stress triggers a global adaptive transcriptional programme.

Felix Boos, Lena Krämer, Carina Groh, Ferris Jung, Per Haberkant, Frank Stein, Florian Wollweber, Adrian Gackstatter, Eva Zöller, Martin van der Laan, Mikhail M Savitski, Vladimir Benes, Johannes M Herrmann.

The cytosolic accumulation of mitochondrial precursors is hazardous to cellular fitness and is associated with a number of diseases. However, it is not observed under physiological conditions. Individual mechanisms that allow cells to avoid cytosolic accumulation of mitochondrial precursors have recently been discovered, but their interplay and regulation remain elusive. Here, we show that cells rapidly launch a global transcriptional programme to restore cellular proteostasis after induction of a 'clogger' protein that reduces the number of available mitochondrial import sites. Cells upregulate the protein folding and proteolytic systems in the cytosol and downregulate both the cytosolic translation machinery and many mitochondrial metabolic enzymes, presumably to relieve the workload of the overstrained mitochondrial import system. We show that this transcriptional remodelling is a combination of a 'wideband' core response regulated by the transcription factors Hsf1 and Rpn4 and a unique mitoprotein-induced downregulation of the oxidative phosphorylation components, mediated by an inactivation of the HAP complex.

DOI: https://doi.org/10.1038/s41556-019-0294-5

EBioMedicine. 2019 Mar 18. pii: S2352-3964(19)30165-3. [Epub ahead of print]

Rapamycin administration is not a valid therapeutic strategy for every case of mitochondrial disease.

Eliana Barriocanal-Casado, Agustín Hidalgo-Gutiérrez, Nuno Raimundo, Pilar González-García, Darío Acuña-Castroviejo, Germaine Escames, Luis C López.

BACKGROUND: The vast majority of mitochondrial disorders have limited the clinical management to palliative care. Rapamycin has emerged as a potential therapeutic drug for mitochondrial diseases since it has shown therapeutic benefits in a few mouse models of mitochondrial disorders. However, the underlying therapeutic mechanism is unclear, the minimal effective dose needs to be defined and whether this therapy can be generally used is unknown.
METHODS: We have evaluated whether low and high doses of rapamycin administration may result in therapeutic effects in a mouse model (Coq9R239X) of mitochondrial encephalopathy due to CoQ deficiency. The evaluation involved phenotypic, molecular, image (histopathology and MRI), metabolomics, transcriptomics and bioenergetics analyses.
FINDINGS: Low dose of rapamycin induces metabolic changes in liver and transcriptomics modifications in midbrain. The high dose of rapamycin induces further changes in the transcriptomics profile in midbrain due to the general inhibition of mTORC1. However, neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics, the brain injuries and the phenotypic characteristics of Coq9R239X mice, resulting in the lack of efficacy for increasing the survival.
INTERPRETATION: These results may be due to the lack of microgliosis-derived neuroinflammation, the limitation to induce autophagy, or the need of a functional CoQ-junction. Therefore, the translation of rapamycin therapy into the clinic for patients with mitochondrial disorders requires, at least, the consideration of the particularities of each mitochondrial disease. FUND: Supported by the grants from "Fundación Isabel Gemio - Federación Española de Enfermedades Neuromusculares - Federación FEDER" (TSR-1), the NIH (P01HD080642) and the ERC (Stg-337327).

Keywords: CoQ deficiency; Mitochondrial diseases; Mitochondrial encephalopathy; Mouse model; mTORC1

DOI: https://doi.org/10.1016/j.ebiom.2019.03.025

BMJ Case Rep. 2019 Mar 20. pii: e227977. [Epub ahead of print]12(3):

Late-onset Leber's hereditary optic neuropathy: the role of environmental factors in hereditary diseases.

Nuno Moura-Coelho, Rita Pinto Proença, Joana Tavares Ferreira, João Paulo Cunha.

Leber's hereditary optic neuropathy (LHON) is an optic neuropathy of mitochondrial inheritance, characterised by incomplete penetrance and variable expressivity. Typically, young male patients present with sequential, severe, rapidly progressive loss of central vision, with characteristic funduscopic findings. However, LHON may present at any age, in both genders, and fundus examination may be normal. Evidence has emerged to support the role of environmental factors in triggering LHON, by disrupting the normal mechanisms of mitochondrial function. We present two clinical cases of LHON of late onset, and provide a literature review on atypical cases of LHON and the role of environmental triggers.

Keywords: genetics; neuroopthalmology; ophthalmology; visual pathway

DOI: https://doi.org/10.1136/bcr-2018-227977