Manjarres-Raza, I. | bioRxiv Science

bioRxiv2024

TET3 regulates cellular terminal differentiation at the metabolic level

TET-family members play an essential role in cell fate commitment and their dysfunctions result in arrested differentiation. TET3 is ubiquitously expressed in differentiated cells and essential in postnatal development due to yet unknown reasons. To define TET3 function in cell differentiation, we profiled the intestinal epithelium at the single-cell level from wild-type and Tet3 knockout mice. Here we show that, in the absence of TET3, enterocytes exhibit an aberrant differentiation trajectory and do not acquire a physiological cell identity due to an impairment in oxidative phosphorylation, specifically due to an ATP synthase assembly deficiency. Furthermore, our analysis demonstrates that the loss of TET3 compromises mitochondrial metabolic maturation and leads to a metabolic profile enriched in glycolysis-dependent anabolic pathways similar to those observed in undifferentiated cells. Collectively, our study has revealed the molecular mechanism by which TET3 regulates terminal differentiation at the metabolic level.

developmental biology↗

bioRxiv2023

Weak neuronal glycolysis sustains cognition and organismal fitness

The energy cost of neuronal activity is mainly sustained by glucose1,2. However, in an apparent paradox, neurons only weakly metabolize glucose through glycolysis3,4,5,6, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (Pfkfb3)3,7,8, a key glycolysis-promoting enzyme. To evaluate the in vivo physiological significance of this hypo-glycolytic metabolism, here we genetically engineered mice with their neurons transformed into active glycolytic cells through Pfkfb3 expression. In vivo molecular, biochemical, and metabolic flux analyses of these neurons revealed an accumulation of anomalous mitochondria, complex I disassembly, bioenergetic deficiency and mitochondrial redox stress. Notably, glycolysis-mediated NAD+ reduction impaired sirtuin-dependent autophagy. Furthermore, these mice displayed cognitive decline and a metabolic syndrome that was mimicked by confining Pfkfb3 expression to hypothalamic neurons. Neuron-specific genetic ablation of mitochondrial redox stress corrected these alterations. Thus, the weak glycolytic nature of neurons is required to sustain higher-order organismal functions.

cell biology↗