bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒03‒21
three papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Neuron. 2021 Mar 17. pii: S0896-6273(21)00121-5. [Epub ahead of print]109(6): 907-909
      In this issue of Neuron, Li et al. (2021) demonstrate that ApoE lipoprotein particles shuttle miRNAs from astrocytes to neurons, leading to inhibition of cholesterol biosynthesis and an increase in histone acetylation in neurons.
  2. JCI Insight. 2021 Mar 11. pii: 144156. [Epub ahead of print]
      Autoimmune diseases are characterized by a breakdown of immune tolerance partly due to environmental factors. The short-chain fatty acid acetate, derived mostly from gut microbial fermentation of dietary fiber, promotes anti-inflammatory regulatory T cells and protects mice from type 1 diabetes, colitis and allergies. Here, we show that the effects of acetate extend to another important immune subset involved in tolerance, the IL-10 producing regulatory B cells (B10 cells). Acetate directly promoted B10 cell differentiation from mouse B1a cells both in vivo and in vitro. These effects were linked to metabolic changes through the increased production of acetyl-CoA, which fueled the tricarboxylic acid cycle and promoted post-translational lysine acetylation. Acetate also promoted B10 cells from human blood cell through similar mechanisms. Finally, we identified that dietary fiber supplementation in healthy individuals was associated with increased blood B10 cells. Direct delivery of acetate or indirectly via acetate-producing diets or -bacteria might be a promising approach to restore B10 cells in non-communicable diseases.
    Keywords:  Beta cells; Immunology; Metabolism
  3. Cell Death Differ. 2021 Mar 15.
      Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the US. Understanding the mechanisms of CRC progression is essential to improve treatment. Mitochondria is the powerhouse for healthy cells. However, in tumor cells, less energy is produced by the mitochondria and metabolic reprogramming is an early hallmark of cancer. The metabolic differences between normal and cancer cells are being interrogated to uncover new therapeutic approaches. Mitochondria targeting PTEN-induced kinase 1 (PINK1) is a key regulator of mitophagy, the selective elimination of damaged mitochondria by autophagy. Defective mitophagy is increasingly associated with various diseases including CRC. However, a significant gap exists in our understanding of how PINK1-dependent mitophagy participates in the metabolic regulation of CRC. By mining Oncomine, we found that PINK1 expression was downregulated in human CRC tissues compared to normal colons. Moreover, disruption of PINK1 increased colon tumorigenesis in two colitis-associated CRC mouse models, suggesting that PINK1 functions as a tumor suppressor in CRC. PINK1 overexpression in murine colon tumor cells promoted mitophagy, decreased glycolysis and increased mitochondrial respiration potentially via activation of p53 signaling pathways. In contrast, PINK1 deletion decreased apoptosis, increased glycolysis, and reduced mitochondrial respiration and p53 signaling. Interestingly, PINK1 overexpression in vivo increased apoptotic cell death and suppressed colon tumor xenograft growth. Metabolomic analysis revealed that acetyl-CoA was significantly reduced in tumors with PINK1 overexpression, which was partly due to activation of the HIF-1α-pyruvate dehydrogenase (PDH) kinase 1 (PDHK1)-PDHE1α axis. Strikingly, treating mice with acetate increased acetyl-CoA levels and rescued PINK1-suppressed tumor growth. Importantly, PINK1 disruption simultaneously increased xenografted tumor growth and acetyl-CoA production. In conclusion, mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming and reducing acetyl-CoA production.