Activity Increase in Respiratory Chain Complexes by Rubella Virus with Marginal Induction of Oxidative Stress

Abstract

bMitochondria are important for the viral life cycle, mainly by providing the energy required for viral replication and assembly. A highly complex interaction with mitochondria is exerted by rubella virus (RV), which includes an increase in the mitochondrial membrane potential as a general marker for mitochondrial activity. We aimed in this study to provide a more comprehensive picture of the activity of mitochondrial respiratory chain complexes I to IV. Their activities were compared among three different cell lines. A strong and significant increase in the activity of mitochondrial respiratory enzyme succinate:ubiquinone oxidoreductase (complex II) and a moderate increase of ubiquinol:cytochrome c oxidoreductase (complex III) were detected in all cell lines. In contrast, the activity of mitochondrial respiratory enzyme cytochrome c oxidase (complex IV) was significantly decreased. The effects on mitochondrial functions appear to be RV specific, as they were absent in control infections with measles virus. Additionally, these alterations of the respiratory chain activity were not associated with an elevated transcription of oxidative stress proteins, and reactive oxygen species (ROS) were induced only marginally. Moreover, protein and/or mRNA levels of markers for mitochondrial biogenesis and structure were elevated, such as nuclear respiratory factors (NRFs) and mitofusin 2 (Mfn2). Together, these results establish a novel view on the regulation of mitochondrial functions by viruses. Mitochondria are required for the maintenance of cell function and integrity. Their most important role lies in energy production, but they are also at the intersection of regulatory pathways that coordinate metabolic processes (e.g., calcium homeostasis and cellular proliferation), cellular fate (apoptosis and necrosis), and antiviral defense (1, 2). Even a participation of mitochondria in the innate immune response was identified (2). There are a number of viruses that interfere with the important role of mitochondria in cellular antiviral response pathways, mainly with the regulation of apoptosis (1). Additionally, as the powerhouses of the cell, mitochondria provide most of the energy for viral replication and assembly. Up to 90% of the cellular ATP is produced in the inner mitochondrial membrane (IMM) by oxidative phosphorylation (OXPHOS), (3). OXPHOS comprises a series of redox reactions carried out by four multisubunit enzyme complexes (complexes I to IV) of the electron transport chain (ETC). Electrons are transferred in a stepwise manner through this series of electron carriers from NADH (and FADH 2 ) as reducing equivalents to the final acceptor molecular oxygen. A small percentage of electrons that are transported through the respiratory complexes leaks out, which results in generation of reactive oxygen species (ROS). The main ROS species is hydrogen peroxide, which is converted to water by enzymes such as catalase, peroxiredoxin, or glutathione peroxidase as components of the cellular antioxidant system. Respiratory c...

The mammalian homologue of yeast Afg1 ATPase (lactation elevated 1) mediates degradation of nuclear-encoded complex IV subunits

“…Thus possibly some of the remaining nuclear-encoded complex III subunit(s) may be affected by LACE1/Afg1 deficiency. The markedly increased activity of complex II is frequently encountered in systems with respiratory chain deficiency where it is thought to serve as a compensatory mechanism for maintaining optimal electron flow through the chain [29,30].…”

Poor maternal nutrition and accelerated postnatal growth induces an accelerated aging phenotype and oxidative stress in skeletal muscle of male rats

“…It has been shown that, in states of ‘mitochondrial hyperactivity’ (in which ETC activities are upregulated), the ETC generates pathologically high ΔΨ m levels, and this mitochondrial hyperpolarization leads to an exponential increase in ROS generation at membrane potentials exceeding 140 mV. This has been demonstrated in many pathologies, including lupus erythematosus (Doherty et al, 2014), rubella infection (Claus et al, 2013) and in multiple sclerosis lesions (Mahad et al, 2009). mRNA levels of Cox1 , one of the three mitochondrially encoded subunits of complex IV of the ETC (Heilbronn et al, 2007), was also upregulated in the skeletal muscle of aged recuperated offspring.…”

Enterovirus 71 Induces Mitochondrial Reactive Oxygen Species Generation That is Required for Efficient Replication

“…It has been recently suggested that the respiratory chain complexes are not arranged simply in a linear order of enzymatic complexes. These complexes display different activities toward one another [74]. Subunits of respiratory complexes differ in their correlation between protein expression and enzymatic activity [75].…”