A bioenergetic shift is required for spermatogonial differentiation

Abstract

A bioenergetic balance between glycolysis and mitochondrial respiration is particularly important for stem cell fate specification. It however remains to be determined whether undifferentiated spermatogonia switch their preference for bioenergy production during differentiation. In this study, we found that ATP generation in spermatogonia was gradually increased upon retinoic acid (RA)-induced differentiation. To accommodate this elevated energy demand, RA signaling concomitantly switched ATP production in spermatogonia from glycolysis to mitochondrial respiration, accompanied by increased levels of reactive oxygen species. Disrupting mitochondrial respiration significantly blocked spermatogonial differentiation. Inhibition of glucose conversion to glucose-6-phosphate or pentose phosphate pathway also repressed the formation of c-Kit + differentiating germ cells, suggesting that metabolites produced from glycolysis are required for spermatogonial differentiation. We further demonstrated that the expression levels of several metabolic regulators and enzymes were significantly altered upon RA-induced differentiation, with both RNAseq and quantitative proteomic analyses. Taken together, our data unveil a critically regulated bioenergetic balance between glycolysis and mitochondrial respiration that is required for spermatogonial proliferation and differentiation.

Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells

“…Upregulation of genes associated with glycolysis and hypoxia was detected in early differentiating spermatogonia of UCH-1 −/− , as opposed to the physiological switch towards OXPHOS in the wild-type. Hence, UCH-L1 deficiency altered the bioenergetic equilibrium between glycolysis and OXPHOS that is necessary for spermatogonial proliferation and differentiation [58]. These data suggest that UCH-L1 is required for maintenance of proper mitochondrial activity and its upregulation leads to impaired function of SSCs, impairing SSC metabolic and differentiation competence.…”

“…It is becoming increasingly evident that maintaining metabolic integrity and plasticity is pivotal for SSC function [33,49,57]. Anaerobic metabolism is necessary for SSC maintenance in vivo and in vitro [33,49], while SSCs upregulate mitochondrial activity with differentiation [40,42,49,58]. The protection of this metabolic balance by preserving the metabolic integrity of SSCs is essential to maintaining the differentiation potential of SSCs, which gradually diminishes in aging cells [58].…”

Colorectal cancer cell intrinsic fibroblast activation protein alpha binds to Enolase1 and activates NF-κB pathway to promote metastasis

“…7E, I ). AP-III-a4 is a non-substrate analog that directly binds to enolase and inhibits its function independent of enzymatic activity, which has been widely used in elucidating the role of ENO1 in many kinds of tumors 24 , 26 , 27 . AP-III-a4 decreased the number of HCT116-FAP and HCT8-FAP cells, and inactivated NF-κB signaling pathway (Fig.…”

Effects of Environmental and Pathological Hypoxia on Male Fertility

“…This is a bioenergenic balance between glycolysis and oxidative phosphorylation, which can be disrupted in the absence of oxygen. Recent research has found that the inhibition of mitochondrial respiration and glycolysis in undifferentiated spermatogonia cells results in decreased spermatogonial colony size, and reduced expression of SSC marker genes, such as Plzf, Id4, Gfrα1, Etv5, and Sall4, suggesting that hypoxia may affect spermatogonia differentiation ( Chen et al, 2020 ).…”