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• W6476725 abstract "Eukaryotic cells are able to continuously adapt to fluctuations in external conditions. Furthermore, when metabolites availability varies, cells undergo rapid changes in order to adapt their metabolism and protect themselves against potential damages. These rapid changes are regulated through different nutrient dependent pathways. The most important proteins, known so far, involved in these pathways are AMPK and Sirtuins. These proteins, that have a key role in the cells response to caloric stress, are activated when the cells are under nutrient deprivation (Dilova et al. 2007). Ca2+ is a fundamental second messenger that enters the cytosol upon the opening of a variety of plasma membrane and endoplasmic/sarcoplasmic reticulum (ER/SR) channels and controls numerous cell functions also at the mitochondrial site (Rizzuto and Pozzan 2006). Foskett’group recently identified a new role of constitutive Ca2+ transfer from ER to mitochondria. They demonstrated that this represents a crucial intracellular signal for AMPK activation and autophagy induction. On the other hand still unknown are the precise physiological signals inside the cell that can translate fluctuation of metabolites concentration into a specific regulation of mitochondrial Ca2+ content (Cardenas et al. 2010).During my PhD, I measured mitochondrial Ca2+ uptake using targeted recombinant aequorin (Pinton et al. 2007). I found that in HeLa cells, after 2 hours of glucose deprivation, mitochondrial Ca2+ uptake is drastically reduced. This physiological response appears to be transient and reversible. Indeed, after glucose deprivation, cells show a reduced mitochondrial Ca2+ uptake up to 4 hours, but after this period it returns to the levels measured in normal feeding conditions. I also investigated the possible involvement of a newly identified regulator of mitochondria Ca2+ uptake, MICU1, and we found that after 2 hours of glucose deprivation this regulator is quickly degraded. Based on its short half-life, we wondered whether during glucose deprivation MICU1 could be ubiquitylated and rapidly degraded. I also found that the proteasome inhibitor MG132 inhibits MICU1 degradation during glucose deprivation and it also increases MICU1 half-life. High-resolution mass spectrometry data reveal five lysines in MICU1 protein sequence that are reported to be ubiquitylated. Thus, I decided to substitute each one of these lysines with one arginine (K>R) in order to generate a MICU1 ubiquitylation incompetent mutant (MICU1K102R, K103R, K104R, K296R, K359R). Importantly, I found that the overexpression of MICU1K102R, K103R, K104R, K296R, K359R partially abolishes the effect of glucose deprivation on mitochondrial Ca2+ uptake. Further experiments will allow us to understand how MICU1 influences the modulation of the activity of mitochondrial Ca2+ transport system. The analysis of this mechanism will allow us to understand if mitochondria can be the link that directly connects glucose availability with the modulation of physio-pathological processes such as autophagy and apoptosis." @default.
• W6476725 created "2016-06-24" @default.
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• W6476725 date "2013-01-29" @default.
• W6476725 modified "2023-09-26" @default.
• W6476725 title "nutrient dependent control of mitochondrial Ca2+ signaling" @default.
• W6476725 hasPublicationYear "2013" @default.
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