title: Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis.
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.
authors.affiliation: Institute of Cellular Biology, University Medical Center Goettingen, Goettingen, Germany.|Doctoral Program on Molecular Medicine, University of Goettingen, Goettingen, Germany.
authors.forename: Lorena
authors.initials: L
authors.lastname: Fernández-Mosquera
authors.affiliation: Institute of Cellular Biology, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Cátia V
authors.initials: CV
authors.lastname: Diogo
authors.affiliation: Institute of Cellular Biology, University Medical Center Goettingen, Goettingen, Germany.|International Max-Planck Research School on Neuroscience, Goettingen, Germany.
authors.forename: King Faisal
authors.initials: KF
authors.lastname: Yambire
authors.affiliation: Institute of Cellular Biology, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Gabriela L
authors.initials: GL
authors.lastname: Santos
authors.affiliation: Departamento de Fisiología, Facultad de Medicina and Instituto de Biotecnología, Centro de Investigación Biomédica, University of Granada, Granada, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Luna Sánchez
authors.affiliation: INSERM UMR 1141, Hôpital Robert Debré, Paris, France.|Faculté de Médecine Denis Diderot, Université Paris Diderot - Paris 7, Site Robert Debré, Paris, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.affiliation: INSERM UMR 1141, Hôpital Robert Debré, Paris, France.|Faculté de Médecine Denis Diderot, Université Paris Diderot - Paris 7, Site Robert Debré, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.affiliation: Departamento de Fisiología, Facultad de Medicina and Instituto de Biotecnología, Centro de Investigación Biomédica, University of Granada, Granada, Spain.
authors.forename: Luis Carlos
authors.initials: LC
authors.lastname: Lopez
authors.affiliation: European Neuroscience Institute, Goettingen, Germany.
authors.forename: Ira
authors.initials: I
authors.lastname: Milosevic
authors.affiliation: Institute of Cellular Biology, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Nuno
authors.initials: N
authors.lastname: Raimundo
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D004579:Electron Transport; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism*; D001678:Organelle Biogenesis; D011494:Protein Kinases / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051739:Microphthalmia-Associated Transcription Factor; C484068:Tcfeb protein, mouse; D014475:Uncoupling Agents; D012402:Rotenone; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases