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  3. Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis

Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis

  • Sci Adv. 2023 May 3;9(18):eadf0115. doi: 10.1126/sciadv.adf0115.
Luke T Izzo 1 2,  Sophie Trefely 1 2 3,  Christina Demetriadou 1 2 3,  Jack M Drummond 1 2,  Takuya Mizukami 4,  Nina Kuprasertkul 1 2 5,  Aimee T Farria 1 2,  Phuong T T Nguyen 1 2,  Nivitha Murali 1 2,  Lauren Reich 1 2,  Daniel S Kantner 3,  Joshua Shaffer 1 2,  Hayley Affronti 1 2,  Alessandro Carrer 1 2,  Andrew Andrews 4 6,  Brian C Capell 5,  Nathaniel W Snyder 3,  Kathryn E Wellen 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3 Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • 4 Department of Cancer Epigenetics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 5 Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6 Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, NC 28403, USA.
PMID: 37134161 DOI: 10.1126/sciadv.adf0115
Abstract

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.

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