bims-meprid 2024-01-14 papers

Issue of 2024‒01‒14
four papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

Nat Metab. 2024 Jan 10.

The serine synthesis pathway drives osteoclast differentiation through epigenetic regulation of NFATc1 expression.

Steve Stegen, Karen Moermans, Ingrid Stockmans, Bernard Thienpont, Geert Carmeliet.

Bone-resorbing osteoclasts are vital for postnatal bone health, as increased differentiation or activity results in skeletal pathologies such as osteoporosis. The metabolism of mature osteoclasts differs from their progenitor cells, but whether the observed metabolic changes are secondary to the altered cell state or actively drive the process of cell differentiation is unknown. Here, we show that transient activation of the serine synthesis pathway (SSP) is essential for osteoclastogenesis, as deletion of the rate-limiting enzyme phosphoglycerate dehydrogenase in osteoclast progenitors impairs their differentiation and results in increased bone mass. In addition, pharmacological phosphoglycerate dehydrogenase inhibition abrogated bone loss in a mouse model of postmenopausal osteoporosis by blocking bone resorption. Mechanistically, SSP-derived α-ketoglutarate is necessary for histone demethylases that remove repressive histone methylation marks at the nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1) gene locus, thereby inducing NFATc1 expression and consequent osteoclast maturation. Taken together, this study reveals a metabolic-epigenetic coupling mechanism that directs osteoclast differentiation and suggests that the SSP can be therapeutically targeted to prevent osteoporotic bone loss.

DOI: https://doi.org/10.1038/s42255-023-00948-y

Cold Spring Harb Perspect Med. 2024 Jan 08. pii: a041537. [Epub ahead of print]

Isocitrate Dehydrogenase Mutations in Cancer: Mechanisms of Transformation and Metabolic Liability.

Kathryn Gunn, Julie-Aurore Losman.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are metabolic enzymes that interconvert isocitrate and 2-oxoglutarate (2OG). Gain-of-function mutations in IDH1 and IDH2 occur in a number of cancers, including acute myeloid leukemia, glioma, cholangiocarcinoma, and chondrosarcoma. These mutations cripple the wild-type activity of IDH and cause the enzymes to catalyze a partial reverse reaction in which 2OG is reduced but not carboxylated, resulting in production of the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). (R)-2HG accumulation in IDH-mutant tumors results in profound dysregulation of cellular metabolism. The most well-characterized oncogenic effects of (R)-2HG involve the dysregulation of 2OG-dependent epigenetic tumor-suppressor enzymes. However, (R)-2HG has many other effects in IDH-mutant cells, some that promote transformation and others that induce metabolic dependencies. Herein, we review how cancer-associated IDH mutations impact epigenetic regulation and cellular metabolism and discuss how these effects can potentially be leveraged to therapeutically target IDH-mutant tumors.

DOI: https://doi.org/10.1101/cshperspect.a041537

Cell Mol Life Sci. 2024 Jan 12. 81(1): 26

Emerging roles of mitochondrial functions and epigenetic changes in the modulation of stem cell fate.

Chensong Zhang, Yang Meng, Junhong Han.

Mitochondria serve as essential organelles that play a key role in regulating stem cell fate. Mitochondrial dysfunction and stem cell exhaustion are two of the nine distinct hallmarks of aging. Emerging research suggests that epigenetic modification of mitochondria-encoded genes and the regulation of epigenetics by mitochondrial metabolites have an impact on stem cell aging or differentiation. Here, we review how key mitochondrial metabolites and behaviors regulate stem cell fate through an epigenetic approach. Gaining insight into how mitochondria regulate stem cell fate will help us manufacture and preserve clinical-grade stem cells under strict quality control standards, contributing to the development of aging-associated organ dysfunction and disease.

Keywords: Epigenetic modifications; Mitochondria; Mitochondria metabolites; Senescence; Stem cell fate

DOI: https://doi.org/10.1007/s00018-023-05070-6

Free Radic Biol Med. 2024 Jan 08. pii: S0891-5849(24)00008-X. [Epub ahead of print]

Oxidative stress and metabolism meet epigenetic modulation in physical exercise.

José Luis García-Giménez, Irene Cánovas-Cervera, Federico V Pallardó.

Physical exercise is established as an important factor of health and generally is recommended for its positive effects on several tissues, organs, and systems. These positive effects come from metabolic adaptations that also include oxidative eustress, in which physical activity increases ROS production and antioxidant mechanisms, although this depends on the intensity of the exercise. Muscle metabolism through mechanisms such as aerobic and anaerobic glycolysis, tricarboxylic acid cycle, and oxidative lipid metabolism can produce metabolites and co-factors which directly impact the epigenetic machinery. In this review, we clearly reinforce the evidence that exercise regulates several epigenetic mechanisms and explain how these mechanisms can be regulated by metabolic products and co-factors produced during exercise. In fact, recent evidence has demonstrated the importance of epigenetics in the gene expression changes implicated in metabolic adaptation after exercise. Importantly, intermediates of the metabolism generated by continuous, acute, moderate, or strenuous exercise control the activity of epigenetic enzymes, therefore turning on or turning off the gene expression of specific programs which can lead to physiological adaptations after exercise.

Keywords: Epigenetics; Oxidative stress; Physical exercise; Redox homeostasis

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.01.008