Role of Mondo/Myc complexes in lifespan regulation Raymond Laboy1,2, Oezlem Karalay1, Adam Antebi1,2 1Max Planck Institute for Biology of Ageing, Cologne, Germany; 2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany
We have previously shown that the transcriptional complex formed by MML-1/MXL-2 is part of an integrated HLH network required for lifespan extension in diverse longevity pathways in Caenorhabditis elegans. These transcription factors are members of the basic helix-loop-helix Myc-like subfamily; MML-1 (Myc and Mondo-like) is homologous to MondoA/ChREBP, whereas MXL-2 is homologous to Max-like. In mammals, complexes formed by MondoA/Mlx and ChREBP/Mlx are activated upon sugar intake and positively regulate glycolysis and lipogenesis. Previous work in our lab demonstrated that HLH-30/TFEB, a conserved regulator of autophagy, lysosome biogenesis and longevity, regulates the nuclear localization of MML-1/MondoA, Conversely, MML-1/MXL-2 regulate HLH-30/TFEB nuclear localization via downregulation of mTOR signaling. Interestingly, both mammalian MondoA and C. elegans MML-1 reside not only in the nucleus, but also at the mitochondria and intracellular vesicles, yet the potential functions within these organelles is not well understood. Consistent with a role in mitochondrial physiology, we found that deletion of mml-1 alters oxygen consumption, ATP production, ROS sensitivity, and fat metabolism. Moreover, homologs of hexokinase, hxk-1 and hxk-2, dramatically affect MML-1 nuclear localization. Currently we are focusing on how hexokinases influence MML-1 and lifespan in different longevity pathways, as well as broadening our search for upstream factors that regulate MML-1 subcellular localization and activity. We will also unravel how these complexes impact organellar physiology, in particular on how they regulate mitochondrial function and carbohydrate metabolism.
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