Title: Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype
Legend: Figure. AT-1 sTg mice are smaller and have a short lifespan. (a) AT-1 sTg mice were generated with an inducible Tet-Off expression system under the control of the Rosa26 locus for systemic overexpression. (b) Western blots showing AT-1 overexpression in different tissues (1, WT; 2, AT-1 sTg). (c) Representative AT-1 sTg mouse and WT littermate when 28 and 55 days old. (d) Body weight of male and female WT and AT-1 sTg mice across their lifespan. (e) Lifespan of AT-1 sTg mice (maximum lifespan, males=142 days, females=147 days, p<0.0005; median lifespan, males=96 days, females=81 days, p<0.0005). (f) Structure illumination microscopy (SIM) of ER in isolated hepatocytes showing size and morphology of sheet-like structures (left panels). SIM showing Fam134b puncta on ER of isolated hepatocytes (right panels). N, nucleus. Data are mean + SD. *p<0.05; #p<0.0005.
Citation: Peng Y, Shapiro SL, Banduseela VC, Dieterich IA, Hewitt KJ, Bresnick EH, Kong G, Zhang J, Schueler KL, Keller MP, Attie AD, Hacker TA, Sullivan R, Kielar-Grevstad E, Arriola Apelo SI, Lamming DW, Anderson RM, Puglielli L. (2018). Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype. Aging Cell, 17(5):e12820. doi: 10.1111/acel.12820.
Abstract: 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 glycaemia, 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.
About the Lab: The Puglielli Lab’s research interests focus on molecular mechanisms of neurodevelopment and neurodegeneration. The laboratory employs a combination of biochemical, cellular, molecular, and genetic approaches in in vitro, ex vivo and in vivo models.