Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis

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.

αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

“…1K-N and S1 ), these data indicate that energy production and/or ROS are not contributing to the observed effect. Recent publications also demonstrated that acetyl-carnitine is a precursor for nuclear acetyl-CoA that supports histone acetylation (Izzo et al, 2023; Kuna et al, 2023). Using a global mass spectrometry approach, we found that knockdown or inhibition of IDH1 decreased global histone acetylation to a greater extent than histone methylation ( Fig.…”

“…To our knowledge, this is the first report of αKG promoting histone acetylation. Histone acetylation is partly controlled by nuclear-cytoplasmic acetyl-CoA pools (Sivanand et al, 2017), and recent work has demonstrated that the endogenous acyl-carrier L-carnitine plays an active role in histone acetylation by shuttling acetyl units in the form of acetylcarnitine from the mitochondria and/or peroxisome and acting as a nuclear acetyl-CoA precursor (Izzo et al, 2023; Kuna et al, 2023). In this study, we have now identified an upstream regulator of the carnitine-histone acetylation axis via the αKGDD TMLHE.…”

“…Prior work has demonstrated that histone acetylation is necessary for HR-mediated DNA repair (Gong and Miller, 2013; Song et al, 2023). Carnitine functions as a carrier for acylgroups into and out of the mitochondria (Longo et al, 2016), and acetylcarnitine shuttling from the mitochondria and peroxisome can provide the acetyl groups for histone acetylation (Izzo et al, 2023; Kuna et al, 2023). Trimethyllysine Hydroxylase Epsilon (TMLHE), an αKGDD, is the first and rate-limiting step in de novo carnitine synthesis but no studies to date have characterized how changes in αKG affect carnitine synthesis or carnitine-dependent processes.…”

A genetically-encoded fluorescent biosensor for visualization of acetyl-CoA in live cells

“…6–8 Acetyl-CoA produced in the mitochondria (or peroxisome) utilizes the carnitine shuttle via carnitine acetyltransferase (CrAT) to translocate into the nucleocytoplasm. 3,9,10 Once the acetyl-carnitine is in the nucleus, carnitine octanoyl transferase (CrOT) 10 converts it back to acetyl-CoA. Acetyl-CoA metabolism is a potential therapeutic target in diseases including cancer, 11–13 metabolic disease, 12,14,15 and neurodegenerative disease.…”

Cytosolic acetyl-CoA synthetase (ACSS2) does not generate butyryl- and crotonyl-CoA

“…The mechanisms underlying the export of these acyl-CoAs from the mitochondrial matrix need to be characterized, but they could rely on the carnitine shuttle system, in particular on the ability of carnitine acetyltransferase (CrAT) to generate a series of acyl-carnitines from short- and medium-chain acyl-CoAs [12]. In support of this model, CrAT-dependent generation of extra-mitochondrial acetyl-CoA [13] was reported.…”