Tsansizi, Lorenza Iolanda (2018) PPM1K, a novel regulator of metabolism and autophagy in the heart. [Ph.D. thesis] Full text disponibile come:
Abstract (italian or english)The general aim of this work was to understand the relationship between mitochondria and autophagy, with a focus on heart biology. Autophagy is of extreme importance for cardiac function. Animal models of impaired autophagy display cardiac phenotypes at basal levels as well as when stressed. In this work we dissected molecularly two different faces of mitochondrial biology related to autophagy: BCAA-catabolism mediated regulation of mTORC1, and the role of the deubiquitinating enzyme USP8, involved in EGFR signaling and mitophagy, in heart mitochondrial function and more generally in heart function. Tissues can adapt to availability of different substrates by activating specific catabolic pathways that in most instances converge on mitochondria. Yet, how fluxes of metabolites through these organelles affect cellular processes is unclear. Here we show that PPM1K, a mitochondrial matrix protein phosphatase that controls the rate limiting step of branched chain amino acid (BCAA) catabolism, modulates mTORC1 activation and autophagy. PPM1K levels directly correlated with increased autophagy and reciprocally, PPM1K was induced upon starvation in vitro and in vivo, including in tissues where BCAA catabolism is considered marginal, like heart. Steady state metabolomics of labeled Leucine metabolites revealed that in the absence of PPM1K, TCA cycle intermediates were as expected decreased, whereas Leucine, its ketoisocaproic ketoacid and surprisingly methionine were increased, potentially explaining the mTORC1 dependent autophagy inhibition. Our data suggest how mitochondrial BCAA catabolism can be sensed by mTORC1 to modulate autophagy.
Abstract (a different language)The general aim of this work was to understand the relationship between mitochondria and autophagy, with a focus on heart biology. Autophagy is of extreme importance for cardiac function. Animal models of impaired autophagy display cardiac phenotypes at basal levels as well as when stressed. In this work we dissected molecularly two different faces of mitochondrial biology related to autophagy: BCAA-catabolism mediated regulation of mTORC1, and the role of the deubiquitinating enzyme USP8, involved in EGFR signaling and mitophagy, in heart mitochondrial function and more generally in heart function. Tissues can adapt to availability of different substrates by activating specific catabolic pathways that in most instances converge on mitochondria. Yet, how fluxes of metabolites through these organelles affect cellular processes is unclear. Here we show that PPM1K, a mitochondrial matrix protein phosphatase that controls the rate limiting step of branched chain amino acid (BCAA) catabolism, modulates mTORC1 activation and autophagy. PPM1K levels directly correlated with increased autophagy and reciprocally, PPM1K was induced upon starvation in vitro and in vivo, including in tissues where BCAA catabolism is considered marginal, like heart. Steady state metabolomics of labeled Leucine metabolites revealed that in the absence of PPM1K, TCA cycle intermediates were as expected decreased, whereas Leucine, its ketoisocaproic ketoacid and surprisingly methionine were increased, potentially explaining the mTORC1 dependent autophagy inhibition. Our data suggest how mitochondrial BCAA catabolism can be sensed by mTORC1 to modulate autophagy.
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