Anabolism-Associated Mitochondrial Stasis Driving Lymphocyte Differentiation over Self-Renewal

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): William C. Adams, Yen-Hua Chen, Radomir Kratchmarov, Bonnie Yen, Simone A. Nish, Wen-Hsuan W. Lin, Nyanza J. Rothman, Larry L. Luchsinger, Ulf Klein, Meinrad Busslinger, Jeffrey C. Rathmell, Hans-Willem Snoeck, Steven L. Reiner
Regeneration requires related cells to diverge in fate. We show that activated lymphocytes yield sibling cells with unequal elimination of aged mitochondria. Disparate mitochondrial clearance impacts cell fate and reflects larger constellations of opposing metabolic states. Differentiation driven by an anabolic constellation of PI3K/mTOR activation, aerobic glycolysis, inhibited autophagy, mitochondrial stasis, and ROS production is balanced with self-renewal maintained by a catabolic constellation of AMPK activation, mitochondrial elimination, oxidative metabolism, and maintenance of FoxO1 activity. Perturbations up and down the metabolic pathways shift the balance of nutritive constellations and cell fate owing to self-reinforcement and reciprocal inhibition between anabolism and catabolism. Cell fate and metabolic state are linked by transcriptional regulators, such as IRF4 and FoxO1, with dual roles in lineage and metabolic choice. Instructing some cells to utilize nutrients for anabolism and differentiation while other cells catabolically self-digest and self-renew may enable growth and repair in metazoa.

Graphical abstract

Teaser

Activated lymphocytes use asymmetric cell division to couple differentiation and self-renewal. Adams et al. show that unequal elimination of aged mitochondria by sibling cells is part of a broader dichotomy of metabolic signaling, which instructs cells to use nutrients for division and differentiation or instead to catabolically self-digest for self-renewal.


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