Lipid signalling drives proteolytic rewiring of mitochondria by YME1L

Thomas MacVicar, Yohsuke Ohba, Hendrik Nolte, Fiona Carola Mayer, Takashi Tatsuta, Hans-Georg Sprenger, Barbara Lindner, Yue Zhao, Jiahui Li, Christiane Bruns, Marcus Krüger, Markus Habich, Jan Riemer, Robin Schwarzer, Manolis Pasparakis, Sinika Henschke, Jens C. Brüning, Nicola Zamboni and Thomas Langer ()
Additional contact information
Thomas MacVicar: Max-Planck-Institute for Biology of Ageing
Yohsuke Ohba: Max-Planck-Institute for Biology of Ageing
Hendrik Nolte: Max-Planck-Institute for Biology of Ageing
Fiona Carola Mayer: Max-Planck-Institute for Biology of Ageing
Takashi Tatsuta: Max-Planck-Institute for Biology of Ageing
Hans-Georg Sprenger: Max-Planck-Institute for Biology of Ageing
Barbara Lindner: University of Cologne
Yue Zhao: University Hospital of Cologne
Jiahui Li: University Hospital of Cologne
Christiane Bruns: University Hospital of Cologne
Marcus Krüger: University of Cologne
Markus Habich: University of Cologne
Jan Riemer: University of Cologne
Robin Schwarzer: University of Cologne
Manolis Pasparakis: Max-Planck-Institute for Biology of Ageing
Sinika Henschke: Max-Planck-Institute for Metabolism Research
Jens C. Brüning: University of Cologne
Nicola Zamboni: Molecular Systems Biology, ETH Zürich
Thomas Langer: Max-Planck-Institute for Biology of Ageing

Nature, 2019, vol. 575, issue 7782, 361-365

Abstract: 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 tumorigenesis1–3. 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.

Date: 2019
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DOI: 10.1038/s41586-019-1738-6

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