Mitochondrial Management of Reactive Oxygen Species: History
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Mitochondria in aerobic eukaryotic cells are both the site of energy production and the formation of harmful species, such as radicals and other reactive oxygen species, known as ROS. They contain an efficient antioxidant system, including low-molecular-mass molecules and enzymes that specialize in removing various types of ROS or repairing the oxidative damage of biological molecules. Under normal conditions, ROS production is low, and mitochondria, which are their primary target, are slightly damaged in a similar way to other cellular compartments, since the ROS released by the mitochondria into the cytosol are negligible. As the mitochondrial generation of ROS increases, they can deactivate components of the respiratory chain and enzymes of the Krebs cycle, and mitochondria release a high amount of ROS that damage cellular structures.

  • oxygen consumption
  • OxPhos
  • ROS generation
  • ROS removal
  • enzymatic antioxidants
  • low-molecular-weight antioxidants

1. Introduction

Mitochondria are double-membrane organelles located in the cells of most eukaryotic organisms, where they perform a wide range of important functions. They contribute to the regulation of intracellular calcium concentration and control the oxidation of fatty acids, as well as being involved in the metabolism of steroids and some amino acids, and the synthesis of urea and phospholipids. However, their main function is to provide most of the energy required for cellular endergonic reactions, such as the synthesis of adenosine 5′-triphosphate (ATP) by the electron transport chain (ETC) and oxidative phosphorylation. This explains why a disturbance of mitochondrial function, due to damage of the mitochondrial components, can cause an impairment of cellular function and even cell death.
The electron flux along the mitochondrial respiratory chain also determines the production of oxygen radicals and other reactive species, referred to as reactive oxygen species (ROS) [1]. ROS include highly reactive species, such as the hydroxyl radical (OH), and species with low reactivity, such as the superoxide (O2•−) and hydrogen peroxide (H2O2). ROS can oxidize and damage cellular components, including mitochondria, altering their functionality.
Mitochondria produce ROS at a rate that depends on cellular pathophysiological conditions and is low under normal conditions. However, mitochondrial antioxidant systems, composed of enzymatic and non-enzymatic antioxidants [2], largely remove ROS produced by mitochondria.
Under conditions where ROS production increases beyond mitochondrial antioxidant capacity, some components of the mitochondrial electronic chain, or Krebs cycle enzymes, may be deactivated. In these conditions, ROS reaching the cytosol also increases, and can be neutralized here by the antioxidant system of the cell or can damage the cellular components [3].
Several sources of ROS are present in the cell, but mitochondria are considered to be their main source [4].
Extensive experimental evidence indicates that the systems that evolved to protect mitochondria against endogenously produced ROS can also scavenge ROS produced from other cellular sources. [5]. This observation indicates that mitochondria can act as an intracellular sink for ROS, which contrasts with the usually recognized role of the organelles as ROS producers.
However, under which conditions and which part of the mitochondrial population performs a sink function is not yet established.

2. Mitochondria Can Remove ROS Produced by Other Cellular Sources

The mitochondrial antioxidant system seems to remove not only the ROS produced by mitochondria but also the O2•− and H2O2 produced in the surrounding medium [5].
The ability of mitochondria to remove H2O2 depends on respiration and is different in the mitochondria of different tissues. Moreover, it changes depending on the metabolic state and the respiratory substrate. Zoccarato et al. showed that brain mitochondria remove exogenous H2O2 faster with malate and glutamate than with succinate as substrates of respiration [249]. Moreover, they found that H2O2 removal in the State 3 of respiration was slightly lower than in State 4. The H2O2 removal supported by succinate is nearly the same in State 4 and State 3 of respiration. They suggested that the H2O2-removing capacity of respiring mitochondria depends primarily on the activities of GPX and GR and that other antioxidant systems only contribute ~20% of detoxifying activity [249].
Later, this idea was questioned by Dreshel and Patel, who found that the glutathione system makes only a minimal contribution to the brain’s mitochondrial removal capacity. Using pharmacological inhibition of mitochondrial antioxidant enzymes, they found that the rate of H2O2 removal only decreased by 25% after GR inhibition, and GPX inhibition had no effect [250]. Conversely, the inhibition of TrxR caused a reduction in the H2O2 removal rates by 80%, and the oxidation of peroxiredoxin lowered this rate by 50%. Non-enzymatic mitochondrial processes also contributed to the removal of hydrogen peroxide but to a lesser extent (estimated to be about 10%) [250].
Other studies showed that also liver mitochondria removed H2O2 and that such removal was verified at higher rates in the presence of respiratory substrates. However, the H2O2 removal rates are similar with succinate or pyruvate/malate, substrates linked to complex II and I, respectively [251] (Venditti et al., 2014). The selective pharmacological inhibition of antioxidant enzymes shows that catalase is the major contributor to H2O2 removal (~31%) and that TrxR and GPX also contribute significantly, but to a lesser extent (~20% and 23%, respectively) [252]. The contribution of non-enzymatic processes to H2O2 removal is about 27% and appears to depend mainly on hemoproteins, as suggested by its changes in the mitochondria of animals with different cytochrome c content [252]. Indeed, it was shown that, in hypothyroid and hyperthyroid conditions, the H2O2 removal rate from liver mitochondria is lower and higher, respectively, compared to the euthyroid ones. These changes were associated with similar changes in cytochrome c content and the contribution of non-enzymatic systems to peroxide removal [252].
During state 4 of respiration, the mitochondria of the heart and liver remove H2O2 at similar rates [253]. In cardiac mitochondria, enzymatic antioxidant systems contribute to the removal of H2O2 to the same extent as hepatic mitochondria, but, unlike the liver, the non-enzymatic system contributes to a greater extent (~36.8%). This effect is consistent with the higher content of hemoproteins [253].

3. Mitochondrial ROS Removal and ROS Signaling

So far, it is established that ROS can regulate various cell signaling pathways and numerous physiological processes [254]. This suggests that maintaining adequate cellular levels of H2O2 is of prime importance for cell function and survival.
The different characteristics of mitochondria render them capable of controlling the cytosolic level of H2O2 [255]. First, mitochondria can maintain high levels of NADPH in the matrix, which is necessary for the activities of most of the H2O2-metabolizing enzymes. To maintain such a high level, the main contribution is due to the respiration-dependent transhydrogenase. Secondly, the resistance of the Prx3 and 5 located in the matrix to oxidative inactivation, unlike cytosolic Prx1, makes the mitochondria capable of removing H2O2 even if H2O2 levels are high. Third, mitochondria possess high amounts of mitochondrial GSH and antioxidant enzymes. For these reasons, it was hypothesized that mitochondria possess several redox mechanisms that allow them to potentially play an important role in the modulation of H2O2-activated signals in the cytosol, facilitating their desensitization [247].

4. Conclusions

Until recently, mitochondria were regarded only for their role as producers of aerobic energy in eukaryotic cells. Indeed, they are the sites of oxidative phosphorylation, the process by which the transfer of electrons from energy substrates to oxygen is coupled with the synthesis of ATP. Later, the observation that the flow of electrons in the respiratory chain also determines the genesis of ROS capable of causing damage to cellular components gave rise to the idea that mitochondria are involved in the degenerative phenomena that cause various diseases and aging.
Subsequently, another role emerged for the mitochondria, as a system capable of protecting the cell from oxidative damage. Indeed, several data suggest that the mitochondrial systems evolved to protect mitochondria from the ROS they produce can also eliminate ROS produced by other cellular sources. It can be hypothesized that this action, which is particularly important in physio-pathological conditions, in which the cellular production of ROS occurs to a greater extent, is more effective in tissues that have an abundant mitochondrial population. Moreover, several experimental evidence, suggested that mitochondria can control the cellular H2O2 levels which make them regulators of the ROS-mediated signaling pathways.

This entry is adapted from the peer-reviewed paper 10.3390/antiox10111824

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