Mitochondrial Pyruvate Metabolism Induces Pseudohypoxia and Mitophagy

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Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Saragsyan, Ahot
Title Mitochondrial Pyruvate Metabolism Induces Pseudohypoxia and Mitophagy
Date 2017
Description Mitochondria play a central role in cellular energy metabolism, and they supply most cellular adenosine triphosphate (ATP). During production of ATP, mitochondria also produce reactive oxygen species that could be damaging to mitochondria and to other cellular compartments. To limit and control the production of excessive reactive oxygen production, mitochondria have developed several quality control mechanisms that ensure mitochondrial integrity. Degradation of mitochondria through autophagy is the last step in mitochondrial quality control. Although mitochondrial dysfunctions are described in many human diseases including neurological diseases, diabetes, and cancer, there is little known about whether mitophagy plays any role in the etiology of these diseases. Partly this could be explained by the fact that for a long time mitophagy has been considered a nonselective process. Now several lines of evidence suggest that mitophagy is a steady state process, and in metabolically active tissues, the half-life of mitochondria is as low as two days. Possibly another reason for the slow progress in mitophagy research has been the lack of easily applicable and sensitive methods for mitophagy detection, and most mitophagic research has been done in settings of extreme mitochondrial stress. For example, carbonyl cyanide m-chlorophenyl hydrazone (CCCP), an uncoupling agent of the mitochondrial proton gradient, has been extensively used. Although CCCP and other global mitochondrial stressors are excellent inducers of mitophagy, they affect the entire mitochondrial pool, and in most cases, do not recapitulate any given physiological or pathophysiological condition. Here we report a sensitive and highly quantifiable method for detection of mitophagy and autophagy in parallel that could be applied to physiological conditions of cells. This method relies on lysosomal delivery of mitochondrial targeted pH-sensitive Rosella biosensors and could reliably detect even very weak induction of mitophagy. Moreover, using this method we identified that pyruvate metabolism in mitochondria induces mitophagy. This mitophagy is mediated by pseudohypoxic induction of hypoxia inducible factor 1?. Interestingly, we discovered that even close to physiological levels of glucose can induce this pathway. Importantly, this process is completely blocked with pharmacological inhibitors of the mitochondrial pyruvate carrier. Thiazolidinediones, a class of insulin sensitizing medications, are known to inhibit the mitochondrial pyruvate carrier. Here, we show that thiazolidinediones are effective inhibitors of pyruvate induced pseudohypoxia. This observation is particularly interesting since thiazolidinediones are actively prescribed. Whether this phenomenon is clinically relevant remains to be studied.
Type Text
Publisher University of Utah
Subject Molecular biology; Cellular biology; Biochemistry
Dissertation Name Doctor of Philosophy
Language eng
Rights Management (c) Ashot Sargsyan
Format Medium application/pdf
ARK ark:/87278/s6dk0774
Setname ir_etd
Date Created 2019-10-17
Date Modified 2019-10-18
ID 1469465
Reference URL
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