Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis

• DOI: 10.1126/sciadv.adf0115
• Publication Date: 2023-05-03T17:58:40Z
• Authors: Luke T. Izzo; Sophie Trefely; Christina Demetri...; Jack M. Drummond; Takuya Mizukami; Nina Kuprasertkul; Aimee T. Farria; Phuong T. T. Nguyen; Nivitha Murali; Lauren Reich; Daniel S. Kantner; Joshua Shaffer; Hayley Affronti; Alessandro Carrer; Andrew Andrews; Brian C. Capell; Nathaniel W. Snyder; Kathryn E. Wellen
• Keywords: Histones; Glucose; Acetyl Coenzyme A; Lipogenesis; Fatty Acids; Acetylation; Biomedicine and Life Sciences; Acetylcarnitine; 3. Good health; Mitochondria

The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation in the nucleus. The two canonical precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It is unclear whether other substantial routes to nuclear-cytosolic acetyl-CoA exist. To investigate this, we generated cancer cell lines lacking both ACLY and ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing, we show that both glucose and fatty acids contribute to acetyl-CoA pools and histone acetylation in DKO cells and that acetylcarnitine shuttling can transfer two-carbon units from mitochondria to cytosol. Further, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and carnitine acetyltransferase (CrAT)-dependent manner. The data define acetylcarnitine as an ACLY- and ACSS2-independent precursor to nuclear-cytosolic acetyl-CoA that can support acetylation, fatty acid synthesis, and cell growth.