Elucidated connection between renal failure and ‘bad’ mitochondria described
Biologists from the A.N. Belozersky Institute of Physico-Chemical Biology, a unit of the Lomonosov Moscow State University suggested the approach to prevent kidney injury after ischemia. Moreover, the scientists explained why these mechanisms become non-protective in kidney of an old organism. The results of the study are published in the Scientific Reports journal.
The project ran by scientists from the A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University is focused on elucidation of mechanisms underlying such severe pathologyas renal failure, caused by ischemia (renal infarct).
Egor Plotnikov, Doctor of Biological Sciences, Professor of the Russian Academy of Sciences, a Leading Researcher at the Laboratory of mitochondria' structure and functions, working at the A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University and one of the corresponding authors of the article, comments: "We've shown that it's possible to prevent kidney damage by its preliminary "training" by short periods of ischemia (blocking of blood supply). However, our main discovery is the fact that this mechanism is disabled in old animals and, as a result, a kidney becomes unprotected. It is extremely important problem as the major part of clinical cases of renal failure occurs in aged patients. To afford the protection of their kidneys would be a great success for medicine".
In experiments young and old rats were used, although what scientists note to get old animals for the experiment is not easy. However, the Institute of Cytology and Genetics, Novosibirsk, provided the Moscow scientists with a unique strain of premature aged rats OXYS, using whose all results and deciphered mechanisms have been proved.
Egor Plotnikov follows: "In the current article we describe what underlies such a loss of adaptation in kidney in old rats (and, probably, in old people). All cells acquire a mechanism of "quality control", which provides removal of damaged cellular elements (in our case — damaged mitochondria) responsible for permanent self-renewal of the system. However, these mechanisms become broken in an old kidney and its adaptive mechanisms stop functioning".
The basic mitochondrial function in any cell, including kidney cells, is energy production. Due to oxidation of substrates, energy is stored in the form of a universal energy form, ATP (Adenosine Triphosphate). A mitochondrion operates as a power-station in the proper sense of the word as initially energy is stored in the inner mitochondrial membrane in the form of electrical potential and only after that it is converted into ATP. Besides that, mitochondria have many other functions: synthesis of some hormones and other substances, detoxification and other functions, including determination of the cell fate – to die or to survive. Moreover, most of these functions are more or less functionally connected with the very electrical transmembrane potential.
The scientists revealed that a considerable number of mitochondria in old rats have lower transmembrane potential and this process inevitably leads to cell death. Since kidney cells can not proliferate, their death becomes irreplaceable and the more they die, the tougher renal injury is. When this happens a kidney is no more able to fulfill its main functions: to remove products of metabolism from the organism, many of which are quite toxic. That's why such "bad" mitochondria should be removed in the process of "quality control". In a young kidney quality control depends on transmembrane potential of mitochondria – when it drops below the critical value for a long time, a mitochondrion gets a "black label" in the form of a special protein — PINK-1. Such a labeled mitochondrion undergoes a process of self-destruction (autophagy) and becomes destroyed in a lysosome (a special organelle, acting as a cellular "stomach"). In cells of old kidneys this process is broken and damaged mitochondria with low potential cannot be destroyed but, on the contrary, are increased in number.
The scientists emphasize: it is possible that they discovered a factor which is a marker of old (or possible premature old) cells. This factor is protein acetylation. In the organ damaged by ischemia the number of proteins to which acetyl group (an acetic acid moiety) is attached significantly increases. But the most important thing is the fact that the number of acetylated proteins in a kidneyrises with aging.
Egor Plotnikov says: "We've shown that training (preconditioning) doesn't work in old age because "bad mitochondria" aren't removed by autophagy. There is the following process: we block blood supply of the kidney (namely, we deprive it of oxygen and substrates) and under these conditions the weakest mitochondria in cells loose their potential and are immediately removed by the quality control system. As a result the "renewal" or just "purges" of mitochondrion population takes place and only the healthy ones survive. That's why in case of severe kidney ischemia mitochondria can cope with the damage and they survive. And what happens in old rats? We do kidney preconditioning, mitochondria loose their potential but they aren't removed as the clean up system operates poorly. As a result of such training "bad" mitochondria are only accumulated in an old cell and in case of kidney ischemia everything gets even worse."
Similar procedures of kidney training are already conducted for people. It has been shown earlier by another scientific group that the mechanism of ischemic or hypoxic training also operates in a human organism. Moreover, clinical practice shows that organs of aged people don't respond to many defensive agents (namely, drugs, simulating preconditioning). As it's quite difficult to cut off blood supply in some organs in a human body (to do so, special surgical intervention in order to constrict renal vessels are needed), so called remote preconditioning (distant training) is used in clinics. This technique allows to interrupt blood supply of an organ (for instance, a muscle) – it looks like arterial blood pressure measurement with using a blood pressure cuff, when an arm or a leg of a patient is squeezed for several minutes. This procedure has not been applied for kidney protection yet, but positive effects for a heart have been observed. However, all these techniques don't work in case of old patients.
Egor Plotnikov concludes: "This project opens a prospect for renal failure treatment. Moreover, mechanisms that we discovered are quite universal, so it's obvious that they are also applicable not only to kidney ischemia, but also to other renal pathologies. It's becoming clear why, on the one hand, aged people suffer from severe kidney injury so often and on the other hand, why most modern treatment methods are helpless when used in case of old people. Our data show the trend for further development of drugs, which could help an old kidney to recover capacity to resist ischemia and increase its adaptation reserves."
The study was supported by the Russian science foundation (RSF) (project 14-15-00147).