Murine cytomegalovirus infection exacerbates complex IV deficiency in a model of mitochondrial disease.

Nicola Ferreira,Kara L Perks,Mariapia A Degli-Esposti,Judith A Ermer,Oliver Rackham,Ambika Periyakaruppiah,Christopher E Andoniou,Jamie K Y Wong,Peter G Noakes,Aleksandra Filipovska,Danielle L Rudler,Giulia Rossetti,Vera Kozjak-Pavlovic

doi:10.1371/journal.pgen.1008604

Abstract

The influence of environmental insults on the onset and progression of mitochondrial diseases is unknown. To evaluate the effects of infection on mitochondrial disease we used a mouse model of Leigh Syndrome, where a missense mutation in the Taco1 gene results in the loss of the translation activator of cytochrome c oxidase subunit I (TACO1) protein. The mutation leads to an isolated complex IV deficiency that mimics the disease pathology observed in human patients with TACO1 mutations. We infected Taco1 mutant and wild-type mice with a murine cytomegalovirus and show that a common viral infection exacerbates the complex IV deficiency in a tissue-specific manner. We identified changes in neuromuscular morphology and tissue-specific regulation of the mammalian target of rapamycin pathway in response to viral infection. Taken together, we report for the first time that a common stress condition, such as viral infection, can exacerbate mitochondrial dysfunction in a genetic model of mitochondrial disease.

Highlights

Mitochondrial diseases (MDs) are a group of progressive tissue-specific or multi-systemic disorders that are caused by defects in energy production [1]
Murine CMV infection exacerbates isolated complex IV deficiency in the heart We investigated the effects of MCMV infection on the abundance of TACO1 and mitochondrial proteins by immunoblotting in the heart and liver of 30 week old mice, and the levels of cytochrome c oxidase subunit 1 (COXI) a key component of the respiratory chain that catalyses the reduction for oxygen to water, which is regulated by TACO1
We identified that infection with murine cytomegalovirus does not trigger an earlier onset of the disease but instead exacerbates the complex IV deficiency and causes alterations in mechanistic target of rapamycin (mTOR) signalling, energy metabolism and neuromuscular morphology

Summary

Introduction

Mitochondrial diseases (MDs) are a group of progressive tissue-specific or multi-systemic disorders that are caused by defects in energy production [1]. Not reported in the literature, in the clinic, MD patients commonly experience progressive deterioration in their clinical symptoms and suffer from profound fatigue and lethargy during infections. This effect is hypothesized to occur due to the large metabolic demand and stress imposed on mitochondria required to provide the necessary energy to overcome infection. MD patients are expected to make a full recovery following infection, in the case of severe infections, prolonged or reoccurring infections, patients may experience permanent regression in their clinical symptoms It remains unknown how environmental stress conditions such as infections could potentially trigger the onset or potentiate the severity of debilitating symptoms suffered by MD patients

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