Reversing the chain The mitochondrial electron transport chain is a major part of cellular metabolism and plays key roles in both cellular respiration and the synthesis of critical metabolites. Typically, electrons flow through the electron transport chain in a specific direction, ending up with oxygen as the terminal electron acceptor. Spinelli et al . characterized an alternative path of electron flow through the transport chain, ending with fumarate as the electron acceptor (see the Perspective by Baksh and Finley). This pathway operates under conditions of limited oxygen availability, and the authors have confirmed its activity in vivo in a mouse model, observing that the propensity to use this pathway varied between organs. —YN

The mTOR complex 1 (mTORC1) kinase regulates cell growth by setting the balance between anabolic and catabolic processes. To be active, mTORC1 requires the environmental presence of amino acids and glucose. While a mechanistic understanding of amino acid sensing by mTORC1 is emerging, how glucose activates mTORC1 remains mysterious. Here, we used metabolically engineered human cells lacking the canonical energy sensor AMPK to identify glucose-derived metabolites required to activate mTORC1 independent of energetic stress. We show that mTORC1 senses a metabolite downstream of the aldolase and upstream of the glyceraldehyde 3-phosphate dehydrogenase steps of glycolysis and pinpoint dihydroxyacetone phosphate (DHAP) as the key molecule. In cells expressing a triose kinase, the synthesis of DHAP from dihydroxyacetone is sufficient to activate mTORC1 even in the absence of glucose. DHAP is a precursor for lipid synthesis, a process under the control of mTORC1, which provides a potential rationale for the sensing of DHAP by mTORC1.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Highlights d Nutritional changes after birth alter b cell function d b cells acquire glucose response via changes in mTORC1 nutrient sensitivity d Glucose response is independent of changes in canonical b cell markers expression d Nutrient-regulated mTORC1 activity controls stem cellderived b cell function