ReviewThe Mitochondrion as a Key Regulator of Ischaemic Tolerance and Injury
Introduction
Pathologies associated with acute circulatory disorders in organs and their consequent complications occupy a leading position as a cause of worldwide mortality. It is estimated more than 17 million people died worldwide from cardiovascular diseases (CVD) in 2008, with three million of these deaths occurring before the age of 60, many of which could have been prevented. The percentage of premature deaths from CVD ranges from 4% in high-income countries to 42% in low-income countries, leading to growing inequalities in the occurrence and outcome of CVD between countries and populations (Fig. 1) [1]. Among the causes of death, stroke takes second place after cardiovascular pathologies, with the consequences of stroke being the leading cause of primary disability. Population studies have shown that less than 15% of patients who have undergone stroke returned back to work or full implementation of their previous domestic responsibilities, with the remaining 85% requiring life-long medical and social support due to their disabilities [2]. In addition, 40-50% of survivors suffer permanent deterioration of cognitive functions such as loss of memory and attention span [3]. Other common pathologies associated with ischaemia are prerenal and renal aetiologies of kidney dysfunction. The mortality rate from acute kidney failure is currently around 22-25% [4]. Despite the development of treatment methods, the number of patients with ischaemic acute renal failure has not reduced [5].
Previous work on ischaemia-reperfusion injury mechanisms indicates that the main damaging effects involve the pathological consequences following restoration of blood flow to the tissue, rather than ischaemia itself. Reperfusion following cessation of blood flow leads to the development of oxidative stress, which is a profound and largely irreversible destructive process leading to the death of reoxygenated cells and may eventually lead to organ failure [6].
Under physiological conditions reactive oxygen species (ROS) formation may vary widely depending on the type of tissue, their functions and conditions (See [7],[8]). In actively proliferating cells and in those which are most often subjected to attacks by pathogens (for example, lung or blood cells) endogenous levels of ROS are high and very much determined by the metabolism and the degree of pathogenic burden, while in poorly metabolising cells with small proliferative potential these levels are much lower. Thus, in actively metabolising tissues such as the brain, heart and kidneys, the problem of homeostasis of ROS is of paramount importance. While ROS play an essential function as intracellular signalling elements, transition to pathological functions of ROS through non-selective oxidative modification of proteins, lipids, nucleic acids and other components of cells and tissues, confer varying degrees of dysfunction. Such a transition as noted earlier involves oxidative stress exceeding the threshold that can be managed by intrinsic mechanisms. However, complete blockade of ROS may also be detrimental, particularly if vital survival or regulatory cell signalling roles of ROS are not served and pathological effects occur causing unnecessary reduction of cellular components (reductive stress, Fig. 2) [9].
Section snippets
ROS and Oxidative Stress - Some Basic Principles Considered
The main regulator of ROS levels in the cell and tissue is oxygen content, which is mostly reliant on active transport in the blood by haemoglobin molecules, in the muscle tissue by myoglobin [10], and in other tissues by physical diffusion of oxygen from the capillaries into the tissue [11], reviewed in Zorov et al. [8]. When oxygen supply to the tissue ceases, tissues with high metabolic requirements very quickly become hypoxic. In turn, cessation of blood flow leading to both the loss of
Mitochondria-directed Therapeutic Approaches
Linear logic for solving this problem has prompted the broad use of antioxidants as pharmaceutical agents for therapy of ischaemic disorders. However such active compounds vary considerably by their mechanisms of actions and targets ultimately affecting the processes of free radical oxidation of cellular structures and biomolecules, including peroxidation of membrane phospholipids. Attempts to achieve therapeutic effect in ischaemic pathologies with the use of antioxidants (vitamins C, E,
Conclusion
Mitochondria are essential components of cells providing numerous bioenergetic, structural and regulatory signalling roles. Cellular and mitochondrial ROS are critical elements in signalling pathways, however under physiologically adverse conditions they may be destructive when they exceeded the normal threshold of ROS levels, as in ischaemia-reperfusion injury. Mitochondria work as a rheostat supporting cellular ROS homeostasis which is a requisite for a normal cell and organ function.
Acknowledgement
The authors’ work is supported by RFBR grants #14-04-00300, 14-04-00542, 13-04-00484, RSF grants 14-15-00107, 14-15-00147, 14-24-00107 and Grant of the President of Russia МК-2508.2014.4.
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