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Título : Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis.
Autor : Fernández-Mosquera, Lorena
Diogo, Cátia V
Yambire, King Faisal
Santos, Gabriela L
Luna Sánchez, Marta
Bénit, Paule
Rustin, Pierre
Lopez, Luis Carlos
Milosevic, Ira
Raimundo, Nuno
MeSH: AMP-Activated Protein Kinase Kinases
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Carbonyl Cyanide m-Chlorophenyl Hydrazone
Electron Transport
HeLa Cells
Mice, Inbred C57BL
Microphthalmia-Associated Transcription Factor
Mitochondrial Diseases
Organelle Biogenesis
Protein Kinases
Uncoupling Agents
Fecha de publicación : 27-mar-2017
Abstract: Mitochondria are key cellular signaling platforms, affecting fundamental processes such as cell proliferation, differentiation and death. However, it remains unclear how mitochondrial signaling affects other organelles, particularly lysosomes. Here, we demonstrate that mitochondrial respiratory chain (RC) impairments elicit a stress signaling pathway that regulates lysosomal biogenesis via the microphtalmia transcription factor family. Interestingly, the effect of mitochondrial stress over lysosomal biogenesis depends on the timeframe of the stress elicited: while RC inhibition with rotenone or uncoupling with CCCP initially triggers lysosomal biogenesis, the effect peaks after few hours and returns to baseline. Long-term RC inhibition by long-term treatment with rotenone, or patient mutations in fibroblasts and in a mouse model result in repression of lysosomal biogenesis. The induction of lysosomal biogenesis by short-term mitochondrial stress is dependent on TFEB and MITF, requires AMPK signaling and is independent of calcineurin signaling. These results reveal an integrated view of how mitochondrial signaling affects lysosomes, which is essential to fully comprehend the consequences of mitochondrial malfunction, particularly in the context of mitochondrial diseases.
URI: http://hdl.handle.net/10668/11008
DOI: 10.1038/srep45076
Aparece en las colecciones: Producción 2020

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