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. Show more
Publication status
publishedExternal links
Journal / series
NatureVolume
Pages / Article No.
Publisher
NatureOrganisational unit
08839 - Zamboni, Nicola (Tit.-Prof.)
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