Congratulations to David Gius, MD, PhD and his lab on their publication in Free Radical Biology and Medicine!
A new paper from the lab of David Gius, MD, PhD, and supported by the Shock Center GeroMetabolism Core, uses a novel mouse model targeting mitochondrial acetylation to identify potential functional mechanisms of ketogenic diets on lipid metabolism. Dr. Gius is a Professor of Radiation Oncology, the Assistant Dean for Research with the Joe R. & Teresa Lozano Long School of Medicine, and the Associate Cancer Center Director with the Mays Cancer Center at UT Health San Antonio MD Anderson.
Mitochondrial ACSS1-K635 acetylation knock-in mice exhibit altered liver lipid metabolism on a ketogenic diet
Guogang Xu, Joseph Schell, Songhua Quan, Yucheng Gao, Sung-Jen Wei, Meixia Pan, Xianlin Han, Guiming Li, Daohong Zhou, Haiyan Jiang, Felix F Dong, Erin Munkácsy, Nobuo Horikoshi, David Gius
Free Radic Biol Med. 2025 Mar 10:232:260-268. doi: 10.1016/j.freeradbiomed.2025.03.009. Online ahead of print.
Abstract:
Acetyl-CoA Synthetase Short Chain Family Member-1 (ACSS1) catalyzes the ligation of acetate and coenzyme A to generate acetyl-CoA in the mitochondria to produce ATP through the tricarboxylic acid (TCA) cycle. We recently generated an ACSS1-acetylation (Ac) mimic knock-in mouse, where lysine 635 was mutated to glutamine (K635Q), which structurally and biochemically mimics an acetylated lysine. ACSS1 enzymatic activity is regulated, at least in part, through the acetylation of lysine 635 in mice (lysine 642 in humans), a Sirtuin 3 deacetylation target. We challenged our Acss1K635Q knock-in mice with a three-week ketogenic diet. While both wild-type and Acss1K635Q knock-in mice were in ketosis with similar blood glucose levels, the Acss1K635Q mice exhibited elevated blood acetate and liver acetyl-CoA. In addition, and importantly, compared to wild-type mice, the liver in the Acss1K635Q mice displayed a much more predominant liver steatosis morphology and accumulation of lipid drops, as measured by H&E and Oil Red O staining. RNAseq analysis identified that genes related to mitochondrial respiratory chain complexes and oxidative stress were significantly overexpressed in the Acss1K635Q mice on a KD. Finally, lipidomics analysis revealed very different lipid profiles for these groups, including a dramatic increase in triacylglycerides (TAGs), phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), and cardiolipins in the Acss1K635Q liver.
Keywords: Acetate; Acetyl-CoA synthetase; Ketogenic diet; Lipid metabolism; Steatosis.