TY - JOUR
T1 - Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype
AU - Peng, Yajing
AU - Shapiro, Samantha L.
AU - Banduseela, Varuna C.
AU - Dieterich, Inca A.
AU - Hewitt, Kyle J.
AU - Bresnick, Emery H.
AU - Kong, Guangyao
AU - Zhang, Jing
AU - Schueler, Kathryn L.
AU - Keller, Mark P.
AU - Attie, Alan D.
AU - Hacker, Timothy A.
AU - Sullivan, Ruth
AU - Kielar-Grevstad, Elle
AU - Arriola Apelo, Sebastian I.
AU - Lamming, Dudley W.
AU - Anderson, Rozalyn M.
AU - Puglielli, Luigi
N1 - Funding Information:
We thank Dr. Albee Messing for critical reading of an early version of this manuscript. We thank Dr. Maria M. Mihaylova and Nicole Cummings for advice on hepatocyte isolation and culture; Dr. Peter Muir, Vicki Kalscheur, and Zhengling Hao at the UW Bone Core Facility for their help with bone analysis; Dr. Brigitte Raabe and Yang Pong for their help with the mouse colony. This work was supported by the NIH (NS094154 and AG053937 to LP; AG057408 to LP and RMA; DK50107 to EHB.; HL113066 and CA152108 to JZ; DK102948 and DK108259 to ADA; AG041765 and AG051974 to DWL); a core grant to the Waisman Center from NICHD‐U54 HD090256; the Glenn Foundation to DWL; and the American Federation for Aging Research to DWL. IAD was supported by T32 AG000213. SIAA was supported in part by the American Diabetes Association. This work was also supported using resources and facilities of the William S. Middleton Memorial Veterans Hospital (Madison, WI). SIM imaging was performed at the Biochemistry Optical Core of the University of Wisconsin‐Madison (Madison, WI).
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
KW - AT-1/SLC33A1
KW - ATase1
KW - ATase2
KW - acetyl-CoA
KW - lysine acetylation
KW - progeria
UR - http://www.scopus.com/inward/record.url?scp=85051070934&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85051070934&partnerID=8YFLogxK
U2 - 10.1111/acel.12820
DO - 10.1111/acel.12820
M3 - Article
C2 - 30051577
AN - SCOPUS:85051070934
VL - 17
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 5
M1 - e12820
ER -