Nature (London), 2019-11, Vol.575 (7782), p.361-365
2019
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- Autor(en) / Beteiligte
- Titel
- Lipid signalling drives proteolytic rewiring of mitochondria by YME1L
- Ist Teil von
- Nature (London), 2019-11, Vol.575 (7782), p.361-365
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Reprogramming of mitochondria provides cells with the metabolic flexibility required to adapt to various developmental transitions such as stem cell activation or immune cell reprogramming, and to respond to environmental challenges such as those encountered under hypoxic conditions or during tumorigenesis 1 – 3 . Here we show that the i -AAA protease YME1L rewires the proteome of pre-existing mitochondria in response to hypoxia or nutrient starvation. Inhibition of mTORC1 induces a lipid signalling cascade via the phosphatidic acid phosphatase LIPIN1, which decreases phosphatidylethanolamine levels in mitochondrial membranes and promotes proteolysis. YME1L degrades mitochondrial protein translocases, lipid transfer proteins and metabolic enzymes to acutely limit mitochondrial biogenesis and support cell growth. YME1L-mediated mitochondrial reshaping supports the growth of pancreatic ductal adenocarcinoma (PDAC) cells as spheroids or xenografts. Similar changes to the mitochondrial proteome occur in the tumour tissues of patients with PDAC, suggesting that YME1L is relevant to the pathophysiology of these tumours. Our results identify the mTORC1–LIPIN1–YME1L axis as a post-translational regulator of mitochondrial proteostasis at the interface between metabolism and mitochondrial dynamics. Under conditions such as hypoxia or starvation, an mTORC1-lipid signalling pathway initiates mitochondrial proteolysis by YME1L.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687DOI: 10.1038/s41586-019-1738-6Titel-ID: cdi_proquest_miscellaneous_2312812261
- Format
- –
- Schlagworte
- 13, 13/109, 13/89, 13/95, 14, 14/34, 14/63, 38, 38/39, 38/91, 631/45/287/1194, 631/45/320, 631/80/474/1768, 631/80/642/333/1465, 64, 82, 82/1, 82/16, 82/29, 82/58, 82/80, 82/83, 96, Acid phosphatase, Adenocarcinoma, Analysis, ATPases Associated with Diverse Cellular Activities - genetics, ATPases Associated with Diverse Cellular Activities - metabolism, Cell activation, Cell growth, Cell Hypoxia, Cell Line, Cell Proliferation, Cellular signal transduction, Humanities and Social Sciences, Humans, Hypoxia, Immune system, Influence, Lipid Metabolism, Lipid transfer proteins, Lipids, Mass spectrometry, Mechanistic Target of Rapamycin Complex 1 - metabolism, Metabolism, Metabolites, Metalloendopeptidases - genetics, Metalloendopeptidases - metabolism, Mitochondria, Mitochondria - metabolism, Mitochondrial Proteins - genetics, Mitochondrial Proteins - metabolism, multidisciplinary, Pancreas, Pancreatic cancer, Peptides, Phosphatidic acid, Phosphatidylethanolamine, Post-translation, Proteases, Proteins, Proteolysis, Proteomes, Proteomics, Rewiring, Science, Science (multidisciplinary), Scientific imaging, Signaling, Spheroids, Stem cells, Structure, Tumors, Xenografts, Xenotransplantation