Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype.

Autor: Peng Y; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.; Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin., Shapiro SL; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.; Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin., Banduseela VC; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.; Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin., Dieterich IA; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.; Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin.; Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin., Hewitt KJ; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin., Bresnick EH; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin., Kong G; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin., Zhang J; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin., Schueler KL; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin., Keller MP; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin., Attie AD; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin., Hacker TA; Cardiovascular Research Center, University of Wisconsin-Madison, Madison, Wisconsin., Sullivan R; Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin., Kielar-Grevstad E; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin., Arriola Apelo SI; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin., Lamming DW; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin., Anderson RM; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.; Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, Wisconsin., Puglielli L; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.; Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin.; Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, Wisconsin.; Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2018 Oct; Vol. 17 (5), pp. e12820. Date of Electronic Publication: 2018 Jul 27.
DOI: 10.1111/acel.12820
Abstrakt: The membrane transporter AT-1/SLC33A1 translocates cytosolic acetyl-CoA into the lumen of the endoplasmic reticulum (ER), participating in quality control mechanisms within the secretory pathway. Mutations and duplication events in AT-1/SLC33A1 are highly pleiotropic and have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity to seizures, and dysmorphism. Despite these known associations, the biology of this key transporter is only beginning to be uncovered. Here, we show that systemic overexpression of AT-1 in the mouse leads to a segmental form of progeria with dysmorphism and metabolic alterations. The phenotype includes delayed growth, short lifespan, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and anemia. In terms of homeostasis, the AT-1 overexpressing mouse displays hypocholesterolemia, altered glycemia, and increased indices of systemic inflammation. Mechanistically, the phenotype is caused by a block in Atg9a-Fam134b-LC3β and Atg9a-Sec62-LC3β interactions, and defective reticulophagy, the autophagic recycling of the ER. Inhibition of ATase1/ATase2 acetyltransferase enzymes downstream of AT-1 restores reticulophagy and rescues the phenotype of the animals. These data suggest that inappropriately elevated acetyl-CoA flux into the ER directly induces defects in autophagy and recycling of subcellular structures and that this diversion of acetyl-CoA from cytosol to ER is causal in the progeria phenotype. Collectively, these data establish the cytosol-to-ER flux of acetyl-CoA as a novel event that dictates the pace of aging phenotypes and identify intracellular acetyl-CoA-dependent homeostatic mechanisms linked to metabolism and inflammation.
(© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje