Inter-organelle crosstalk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress

Abstract

Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several25 organelle-specific pathways are available for provision of acetyl-CoA as nutrient availability26 fluctuates, so understanding how cells maintain acetyl-CoA flux under such stresses is critically27 important. To this end we applied 13 C isotope tracing cell lines deficient in these mitochondrial28 (ATP-citrate lyase; ACLY-), cytosolic, (acetyl-CoA synthetase (ACSS2-), and peroxisomal29 (peroxisomal biogenesis factor 5; PEX5-) dependent pathways. ACLY knockout in multiple cell30 lines reduced fatty acid synthesis and increased reliance on extracellular lipids or acetate. Knockout31 of both ACLY and ACSS2 (DKO) severely stunted but did not entirely block proliferation,32 suggesting alternate pathways can support acetyl-CoA homeostasis. Metabolic tracing and PEX533 knockout studies link peroxisomal oxidation of exogenous lipids as a major source of acetyl-CoA34 for lipogenesis and histone acetylation, highlighting a role for inter-organelle crosstalk in35 supporting cell survival in response to nutrient fluctuations.