Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis

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 in-vestigate 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 car-nitine acetyltransferase (CrAT)-dependent manner. The data define acetylcarnitine as an ACLY-and ACSS2-in-dependent precursor to nuclear-cytosolic acetyl-CoA that can support acetylation, fatty acid synthesis, and cell growth.

Automated summary

The metabolite acetyl-CoA is essential for lipid synthesis and histone acetylation. Citrate and acetate are the primary precursors for nuclear-cytoplasmic acetyl-CoA. This study shows that glucose and fatty acids can contribute to acetyl-CoA pools and histone acetylation, and acetylcarnitine can transport two-carbon units from mitochondria to the cytosol. Glucose can also support fatty acid synthesis in the absence of ACLY, through a carnitine responsive and carnitine acetyltransferase-dependent mechanism.