Review article
Functional role of mitochondrial reactive oxygen species in physiology

https://doi.org/10.1016/j.freeradbiomed.2016.06.005Get rights and content

Highlights

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    Mitochondria produce and modify ROS in response to physical and chemical stimuli.

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    Mitochondria are able to sense changes in atmospheric O2 and produce ROS to hypoxia.

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    Mitochondrial ROS can induce lipid peroxidation and activate PLC-induced Ca2+ signal.

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    Superoxide from mitochondria can modify activity of ion channels and receptors.

Abstract

The major energy generator in the cell – mitochondria produce reactive oxygen species as a by-product of a number of enzymatic reactions and the production of ATP. Emerging evidence suggests that mitochondrial ROS regulate diverse physiological parameters and that dysregulated ROS signalling may contribute to a development of processes which lead to human diseases. ROS produced in mitochondrial enzymes are triggers of monoamine-induced calcium signal in astrocytes, playing important role in physiological and pathophysiological response to dopamine. Generation of ROS in mitochondria leads to peroxidation of lipids, which is considered to be one of the most important mechanisms of cell injury under condition of oxidative stress. However, it also can induce activation of mitochondrial and cellular phospholipases that can trigger a variety of the signals – from activation of ion channels to stimulation of calcium signal. Mitochondria are shown to be the oxygen sensor in astrocytes, therefore inhibition of respiration by hypoxia induces ROS production which leads to lipid peroxidation, activation of phospholipase C and induction of IP3-mediated calcium signal. Propagation of astrocytic calcium signal stimulates breathing activity in response to hypoxia. Thus, ROS produced by mitochondrial enzymes or electron transport chain can be used as a trigger for signalling cascades in central nervous system and deregulation of this process leads to pathology.

Introduction

Although mitochondria have multiple important functions, these organelles are mainly high efficient engine for conversion of the products of glucose or fatty acid metabolism into universal form of energy which is accepted by all types of cells – ATP. As in every highly efficient engine, the process of ATP production in the oxidative phosphorylation coupled with the mitochondrial respiration in the electron transport chain is having a leakage of energy in the [1] form of electrons. These outgoing electrons can hit the nearby situated molecules and ultimately produce free radicals. Mitochondria are using most of the oxygen taken up by the cell and considering this oxygen-rich environment, the production of Reactive Oxygen Species (ROS) is inevitable. Electrons escaping the electron transport chain in the first instance generate ROS mainly in the form of super oxide radical O2·−. This superoxide is converted to hydrogen peroxide [2], [3], [4].

Compared to the activated enzymes such as NADPH oxidases or xanthine oxidase mitochondria produce less ROS, but in contrast to any other enzymatic and non-enzymatic ROS producer, this organelles are able to generate free radicals continually [5]. Considering the high activity and toxicity of some forms of ROS, our cells (and particularly the mitochondria) in the time of evolution have not only developed effective defence systems against oxidative damage but also adopted ROS to play signalling and regulatory role in physiological processes.

The rate of production and the level of ROS produced by mitochondria can be modulated by a number of factors that render this system to be an ideal regulatory instrument in the cellular homeostasis and to be a messenger in the signal transduction cascades. Additionally, some misfolded proteins that play role in neurodegeneration (including alpha-synuclein, beta-amyloid and tau) could have an effect on mitochondrial function [6], [7] and ROS production; moreover, oligomeric form of alpha-synuclein in combination with metal ions can induce superoxide and hydrogen peroxide production [8], [9].

In the following review we discuss the physiological role of ROS produced in the mitochondria and how deregulation of this processes can lead to a development of pathology and become trigger of cell death (which is as well one of the multiple mitochondrial functions).

Section snippets

Mitochondrial ROS producers

In the majority of publications under the term “mitochondrial ROS” the authors mean the ROS produced in the electron transport chain (ETC) of the mitochondria. However, ROS in mitochondria can be formed by enzymatic action of numerous enzymes including monoamine oxidase (MAO) and cytochrome b5 reductase (Cb5R) located on the outer mitochondrial membrane, as well as glycerol-3-phosphate dehydrogenase and in some cell types or various cytochrome P450 enzymes located in the inner mitochondrial

Mitochondrial ROS as activators of phospholipases

Phospholipases play housekeeping and signalling roles in the cells. It has been demonstrated that ROS production could activate phospholipases [32]. This activating effect has been shown for different forms of ROS including the product of oxidative stress – lipid peroxidation [33], [34], [35]. Lipid peroxidation is affecting different isoforms of phospholipase A in mitochondria, cytosol and lysosomes. Stimulating effect of lipid peroxidation has been also shown for phospholipase D [36] and,

Conclusion remarks

For long time reactive oxygen species have been considered to be by-products of biological reactions that are highly aggressive and damaging to the surrounding tissue. It is necessary to accentuate on the fact that ROS are not cellular waste products, but actually signalling molecules that are very important for proper functioning of the organism, including proliferation, differentiation, aging, transcription factor regulation, inflammation, and other regulatory functions.

There are no doubts

Acknowledgment

We thank Leverhulme Trust for support.

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