Mitochondrial Na+/Ca2+ exchanger (NCLX) in nutrient sensing pathways: regulation of autophagy and mTORC1 signaling
Intracellular signaling mediated by calcium ions (Ca2+) is a central aspect in the regulation of innumerous cellular processes, including metabolism, proliferation, and cell death. Mitochondria play a central role in Ca2+ homeostasis, as they are capable of taking up, retaining, and releasing these...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | Brasil |
| Institución: | Universidade de São Paulo (USP) |
| Repositorio: | Biblioteca Digital de Teses e Dissertações da USP |
| Idioma: | inglés |
| OAI Identifier: | oai:teses.usp.br:tde-04072025-094533 |
| Acceso en línea: | https://www.teses.usp.br/teses/disponiveis/46/46131/tde-04072025-094533/ |
| Access Level: | acceso abierto |
| Palabra clave: | Amino acids Aminoácidos Autofagia Autophagy Cálcio Calcium mTORC1 NCLX |
| Sumario: | Intracellular signaling mediated by calcium ions (Ca2+) is a central aspect in the regulation of innumerous cellular processes, including metabolism, proliferation, and cell death. Mitochondria play a central role in Ca2+ homeostasis, as they are capable of taking up, retaining, and releasing these ions. This influences not only their own functions but also the signaling of Ca2+-dependent pathways within the cell. The influx of Ca2+ into mitochondria occurs through the mitochondrial calcium uniporter complex (MCUc), while efflux is partly controlled by the mitochondrial Na+/Li+/Ca2+ exchanger (NCLX). Recent studies demonstrated the critical importance of NCLX activity in maintaining both mitochondrial and cellular Ca2+ homeostasis. Dysfunction of this transporter leads to a variety of adverse consequences for numerous cellular processes. However, the regulation of NCLX in response to nutrient availability and its impact on the cellular pathways operating within this context have not yet been thoroughly explored. In this regard, cells require adaptive mechanisms to respond to fluctuations in nutrient availability; mitochondria and Ca2+ signaling are essential for these processes. This thesis investigates the role of NCLX in nutrient sensing cellular pathways, with an emphasis on autophagy and the mTORC1 pathway. Our main findings demonstrate that NCLX activity is crucial in the regulation of autophagy, both under basal conditions and during nutrient deprivation. This is mediated by the modulation of Ca2+ signaling. Additionally, the inhibition of NCLX results in an increased activity of mTORC1, possibly due to effects on the lysosomal machinery that regulates this pathway. These results suggest that NCLX is not only critical to maintain Ca2+ homeostasis, but also plays a significant physiological role in cellular adaptation to nutrient restriction. Thus, the research presented in this thesis contributes to a deeper understanding of the interactions between Ca2+ signaling, mitochondria, and nutrient-dependent adaptive responses, highlighting the importance of NCLX in metabolic signaling pathways. |
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