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Sci Rep. 2017 Mar 27;7:45076. doi: 10.1038/srep45076.

Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis.

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Institute of Cellular Biology, University Medical Center Goettingen, Goettingen, Germany.
Doctoral Program on Molecular Medicine, University of Goettingen, Goettingen, Germany.
International Max-Planck Research School on Neuroscience, Goettingen, Germany.
Departamento de Fisiología, Facultad de Medicina and Instituto de Biotecnología, Centro de Investigación Biomédica, University of Granada, Granada, Spain.
INSERM UMR 1141, Hôpital Robert Debré, Paris, France.
Faculté de Médecine Denis Diderot, Université Paris Diderot - Paris 7, Site Robert Debré, Paris, France.
European Neuroscience Institute, Goettingen, Germany.


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.

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