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

Abstract

SUMMARY 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.

Expanding perspectives on the significance of mitophagy in cancer

“…3). Related findings have been reported in the lymphoid system where accumulation of older mitochondria promoted differentiation of B and T cells at the expense of self-renewing lymphoid progenitors [169]. However, the role of mitochondrial fission in segregation of young and old mitochondria to stem versus non-stem daughter cells clearly requires more investigation, particularly in light of recent data showing that mdivi targets complex I of the respiratory chain [170] and the known role for ROS in cell fate determination [145,171].…”

“…By eliminating dysfunctional or aged mitochondria, mitophagy undoubtedly influences the signaling capacity of the mitochondria and indeed the ultimate consequence of defective mitochondria is a terminal cell fate, namely cell death [149]. However, recent evidence indicates that reduced mitophagy also contributes to loss of stemness and modulates differentiation rates within tissues [9,168,169]. Mitochondria are asymmetrically divided in immortalized human mammary epithelial stem cells with younger mitochondria segregating preferentially to stem-like daughter cells with mammosphere-forming capacity [168].…”

“…3) [169,172–174]. This block to respiration and oxidative metabolism is driven by HIF activity in the hypoxic environment in which stem cells frequently reside [173].…”

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

“…Thus, it may be advantageous for tissue-resident Tmem cells to maintain lower mTOR activity in favor of metabolic regulators such as AMPK, which can help lymphocytes manage stress and metabolic resources to promote long-term survival until recalled (Blagih et al, 2015). Consistent with this, activated B cells with asymmetric clustering of AMPK activity display increased mitochondrial turnover and escape immune senescence (Adams et al, 2016). AMPK may achieve this in part by suppressing mTORC1 activity in T cells (Blagih et al, 2015; Rolf et al, 2013).…”

“…Recent findings have revealed that this process is marked by the segregation of key molecular components into each daughter cell, with mTORC1, c-Myc, and amino acid transporters accumulating in the cell destined to become an effector cell (Figure 2). This is accompanied by an increase in glycolytic rate, and contrasts with the other daughter cell destined to become a Tmem cell, where mTORC1 and c-Myc are by comparison sparse and oxidative phosphorylation is emphasized (Adams et al, 2016; Pollizzi et al, 2016; Verbist et al, 2016). Asymmetric inheritance of mTORC1 has an impact on lymphocyte metabolic fitness, with mTORC1 lo daughter cells displaying increased SRC and better long-term in vivo survival than Teff cell counterparts with high mTORC1 activity (Pollizzi et al, 2016).…”