bims-meprid 2025-03-23 papers

Annu Rev Biochem. 2025 Mar 17.

Moonlighting Enzymes at the Interface Between Metabolism and Epigenetics.

Metabolism and gene regulation are vital processes that need to be tightly coordinated to maintain homeostasis or to enable growth and development. Recent research has begun to reveal the surprisingly interlaced relationship between metabolism and gene expression control. Because key metabolites are cofactors or cosubstrates of chromatin-modifying enzymes, changes in their concentrations can modulate chromatin states and gene expression. Additionally, an increasing number of key metabolic enzymes are found to directly regulate chromatin and transcription in response to changes in metabolic state. These include enzymes that fuel chromatin-associated metabolism and moonlighting enzymes that function as transcription factors, independent of their enzymatic activity. Conversely, accumulating evidence suggests that chromatin itself serves key metabolic functions, independent of transcriptional regulation. Here, we discuss the bidirectional interface between metabolism and chromatin and its corruption in cancer cells.

DOI: https://doi.org/10.1146/annurev-biochem-030122-044718

Sci Adv. 2025 Mar 21. 11(12): eads9182

A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells.

Lipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor-negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer.

DOI: https://doi.org/10.1126/sciadv.ads9182

Nat Commun. 2025 Mar 15. 16(1): 2557

Regulation of acetyl-CoA biosynthesis via an intertwined acetyl-CoA synthetase/acetyltransferase complex.

Liujuan Zheng, Yifei Du, Wieland Steinchen, Mathias Girbig, Frank Abendroth, Ekaterina Jalomo-Khayrova, Patricia Bedrunka, Isabelle Bekeredjian-Ding, Christopher-Nils Mais, Georg K A Hochberg, Johannes Freitag, Gert Bange.

Acetyl-CoA synthetase (Acs) generates acetyl-coenzyme A (Ac-CoA) but its excessive activity can deplete ATP and lead to a growth arrest. To prevent this, Acs is regulated through Ac-CoA-dependent feedback inhibition executed by Ac-CoA-dependent acetyltransferases such as AcuA in Bacillus subtilis. AcuA acetylates the catalytic lysine of AcsA turning the synthetase inactive. Here, we report that AcuA and AcsA form a tightly intertwined complex - the C-terminal domain binds to acetyltransferase domain of AcuA, while the C-terminus of AcuA occupies the CoA-binding site in the N-terminal domain of AcsA. Formation of the complex reduces AcsA activity in addition to the well-established acetylation of the catalytic lysine 549 in AcsA which we show can disrupt the complex. Thus, different modes of regulation accomplished through AcuA adjust AcsA activity to the concentrations of the different substrates of the reaction. In summary, our study provides detailed mechanistic insights into the regulatory framework underlying acetyl-CoA biosynthesis from acetate.

DOI: https://doi.org/10.1038/s41467-025-57842-2

Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00201-3. [Epub ahead of print]44(3): 115430

Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.

Beibei Wu, Jin Seok Woo, Spyridon Hasiakos, Calvin Pan, Shawn Cokus, Cristiane Benincá, Linsey Stiles, Zuoming Sun, Matteo Pellegrini, Orian S Shirihai, Aldon J Lusis, Sonal Srikanth, Yousang Gwack.

Genetic and environmental factors shape an individual's susceptibility to autoimmunity. To identify genetic variations regulating effector T cell functions, we used a forward genetics screen of inbred mouse strains and uncovered genomic loci linked to cytokine expression. Among the candidate genes, we characterized a mitochondrial inner membrane protein, TMEM11, as an important determinant of Th1 responses. Loss of TMEM11 selectively impairs Th1 cell functions, reducing autoimmune symptoms in mice. Mechanistically, Tmem11-/- Th1 cells exhibit altered cristae architecture, impaired respiration, and increased mitochondrial reactive oxygen species (mtROS) production. Elevated mtROS hindered histone acetylation while promoting neutral lipid accumulation. Further experiments using genetic, biochemical, and pharmacological tools revealed that mtROS regulate acetyl-CoA flux between histone acetylation and fatty acid synthesis. Our findings highlight the role of mitochondrial cristae integrity in directing metabolic pathways that influence chromatin modifications and lipid biosynthesis in Th1 cells, providing new insights into immune cell metabolism.

Keywords: CP: Immunology; CP: Metabolism; EAE; MICOS complex; Th1 cells; cytokine production; histone acetylation; mitochondria; mitochondrial cristae architecture; neutral lipids; reactive oxygen species

DOI: https://doi.org/10.1016/j.celrep.2025.115430

Nat Commun. 2025 Mar 18. 16(1): 2663

HSD17B4 deficiency causes dysregulation of primary cilia and is alleviated by acetyl-CoA.

Ji-Eun Bae, Soyoung Jang, Joon Bum Kim, Na Yeon Park, Doo Sin Jo, Hyejin Hyung, Pansoo Kim, Min-Seon Kim, Hong-Yeoul Ryu, Hyun-Shik Lee, Dong-Seok Lee, Myriam Baes, Zae Young Ryoo, Dong-Hyung Cho.

Primary cilia are dynamic sensory organelles orchestrating key signaling pathways, and disruption of primary ciliogenesis is implicated in a spectrum of genetic disorders. The peroxisomal bifunctional enzyme HSD17B4 is pivotal for peroxisomal β-oxidation and acetyl-CoA synthesis, and its deficiency profoundly impairs peroxisomal metabolism. While patients with HSD17B4 deficiency exhibit ciliopathy-like symptoms due to dysfunctional primary cilia, the molecular connection between HSD17B4 and ciliopathy remains poorly understood. Here, we demonstrate that HSD17B4 deficiency impairs primary ciliogenesis and alters cilia-mediated signaling, suggesting a potential link between peroxisomal metabolism and ciliary function. Notably, elevation of acetyl-CoA rescues ciliary defects via HDAC6-mediated ciliogenesis in HSD17B4-deficient cells. Strikingly, acetate administration restores motor function, enhances primary cilia formation, and preserves the Purkinje layer in Hsd17B4-knockout mice. These findings provide insights into the functional link between HSD17B4 and primary cilia, highlighting acetyl-CoA as a potential therapeutic target for HSD17B4 deficiency and ciliopathy.

DOI: https://doi.org/10.1038/s41467-025-57793-8

bioRxiv. 2025 Mar 07. pii: 2025.03.03.641255. [Epub ahead of print]

Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.

Ayşegül Erdem, Séléna Kaye, Francesco Caligiore, Manuel Johanns, Fleur Leguay, Jan Jacob Schuringa, Keisuke Ito, Guido Bommer, Nick van Gastel.

Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+. We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry. Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition. Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.

DOI: https://doi.org/10.1101/2025.03.03.641255