Universität zu Köln

MacVicar, Thomas, Ohba, Yohsuke, Nolte, Hendrik, Mayer, Fiona Carola, Tatsuta, Takashi, Sprenger, Hans-Georg, Lindner, Barbara, Zhao, Yue, Li, Jiahui, Bruns, Christiane, Krueger, Marcus, Habich, Markus, Riemer, Jan, Schwarzer, Robin, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Henschke, Sinika, Bruening, Jens C., Zamboni, Nicola ORCID: 0000-0003-1271-1021 and Langer, Thomas (2019). Lipid signalling drives proteolytic rewiring of mitochondria by YME1L. Nature, 575 (7782). S. 361 - 386. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code MacVicar, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Ohba, Yohsuke UNSPECIFIED UNSPECIFIED UNSPECIFIED Nolte, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayer, Fiona Carola UNSPECIFIED UNSPECIFIED UNSPECIFIED Tatsuta, Takashi UNSPECIFIED UNSPECIFIED UNSPECIFIED Sprenger, Hans-Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Lindner, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Yue UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Jiahui UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruns, Christiane UNSPECIFIED UNSPECIFIED UNSPECIFIED Krueger, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Habich, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Riemer, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarzer, Robin UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Henschke, Sinika UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruening, Jens C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zamboni, Nicola UNSPECIFIED orcid.org/0000-0003-1271-1021 UNSPECIFIED Langer, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-127653
DOI:	10.1038/s41586-019-1738-6
Journal or Publication Title:	Nature
Volume:	575
Number:	7782
Page Range:	S. 361 - 386
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-4687
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MTOR; PHOSPHORYLATION; METABOLISM; ACTIVATION; EXTRACTION; TRANSPORT; PROTEINS; COMPLEX; FUSION; GROWTH Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12765