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@ARTICLE{Jackson:164042,
author = {Jackson, Joshua and Wischhof, Lena and Scifo, Enzo and
Pellizzer, Anna and Wang, Yiru and Piazzesi, Antonia and
Gentile, Debora and Siddig, Sana and Stork, Miriam and
Hopkins, Chris E and Händler, Kristian and Weis, Joachim
and Roos, Andreas and Schultze, Joachim L and Nicotera,
Pierluigi and Ehninger, Dan and Bano, Daniele},
title = {{SGPL}1 stimulates {VPS}39 recruitment to the mitochondria
in {MICU}1 deficient cells.},
journal = {Molecular metabolism},
volume = {61},
issn = {2212-8778},
address = {Oxford [u.a.]},
publisher = {Elsevier},
reportid = {DZNE-2022-00705},
pages = {101503},
year = {2022},
abstract = {Mitochondrial 'retrograde' signaling may stimulate
organelle biogenesis as a compensatory adaptation to
aberrant activity of the oxidative phosphorylation (OXPHOS)
system. To maintain energy-consuming processes in OXPHOS
deficient cells, alternative metabolic pathways are
functionally coupled to the degradation, recycling and
redistribution of biomolecules across distinct intracellular
compartments. While transcriptional regulation of
mitochondrial network expansion has been the focus of many
studies, the molecular mechanisms promoting mitochondrial
maintenance in energy-deprived cells remain poorly
investigated.We performed transcriptomics, quantitative
proteomics and lifespan assays to identify pathways that are
mechanistically linked to mitochondrial network expansion
and homeostasis in Caenorhabditis elegans lacking the
mitochondrial calcium uptake protein 1 (MICU-1/MICU1). To
support our findings, we carried out biochemical and image
analyses in mammalian cells and mouse-derived tissues.We
report that micu-1(null) mutations impair the OXPHOS system
and promote C. elegans longevity through a transcriptional
program that is independent of the mitochondrial calcium
uniporter MCU-1/MCU and the essential MCU regulator
EMRE-1/EMRE. We identify sphingosine phosphate lyase
SPL-1/SGPL1 and the ATFS-1-target HOPS complex subunit
VPS-39/VPS39 as critical lifespan modulators of micu-1(null)
mutant animals. Cross-species investigation indicates that
SGPL1 upregulation stimulates VPS39 recruitment to the
mitochondria, thereby enhancing mitochondria-lysosome
contacts. Consistently, VPS39 downregulation compromises
mitochondrial network maintenance and basal autophagic flux
in MICU1 deficient cells. In mouse-derived muscles, we show
that VPS39 recruitment to the mitochondria may represent a
common signature associated with altered OXPHOS system.Our
findings reveal a previously unrecognized SGPL1/VPS39 axis
that stimulates intracellular organelle interactions and
sustains autophagy and mitochondrial homeostasis in OXPHOS
deficient cells.},
keywords = {Aldehyde-Lyases: metabolism / Animals / Autophagy-Related
Proteins: metabolism / Caenorhabditis elegans /
Caenorhabditis elegans Proteins: metabolism /
Calcium-Binding Proteins: genetics / Calcium-Binding
Proteins: metabolism / Mice / Mitochondria: metabolism /
Mitochondrial Membrane Transport Proteins: metabolism /
Oxidative Phosphorylation / Vesicular Transport Proteins:
metabolism / Autophagy (Other) / Caenorhabditis elegans
(Other) / Longevity (Other) / MICU1 (Other) / Mitochondria
(Other) / Sphingosine signaling (Other) / VPS39 (Other)},
cin = {AG Bano / AG Ehninger / AG Schultze / $R\&D$ PRECISE},
ddc = {610},
cid = {I:(DE-2719)1013003 / I:(DE-2719)1013005 /
I:(DE-2719)1013031 / I:(DE-2719)5000031},
pnm = {351 - Brain Function (POF4-351) / 352 - Disease Mechanisms
(POF4-352) / 354 - Disease Prevention and Healthy Aging
(POF4-354)},
pid = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-352 /
G:(DE-HGF)POF4-354},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC9170783},
pubmed = {pmid:35452878},
doi = {10.1016/j.molmet.2022.101503},
url = {https://pub.dzne.de/record/164042},
}