Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming

Abstract

SUMMARY Activated effector T (TE) cells augment anabolic pathways of metabolism, such as aerobic glycolysis, while memory T (TM) cells engage catabolic pathways, like fatty acid oxidation (FAO). However, signals that drive these differences remain unclear. Mitochondria are metabolic organelles that actively transform their ultrastructure. Therefore, we questioned whether mitochondrial dynamics controls T cell metabolism. We show that TE cells have punctate mitochondria, while TM cells maintain fused networks. The fusion protein Opa1 is required for TM, but not TE cells after infection and enforcing fusion in TE cells imposes TM cell characteristics and enhances antitumor function. Our data suggest that, by altering cristae morphology, fusion in TM cells configures electron transport chain (ETC) complex associations favoring oxidative phosphorylation (OXPHOS) and FAO, while fission in TE cells leads to cristae expansion, reducing ETC efficiency and promoting aerobic glycolysis. Thus, mitochondrial remodeling is a signaling mechanism that instructs T cell metabolic programming.

The mitochondrial dynamics in cancer and immune-surveillance

“…As regards the anti-tumor T cell response, forcing mitochondrial fusion during in vitro T cell expansion promotes differentiation of naïve T cells toward a memory phenotype, as recently demonstrated [202]. This can confer a higher survival to these cells during ACI.…”

“…By contrast, memory T cells (T M ) switch towards fatty-acid oxidation to sustain their metabolism and self-renewal, thus increasing their mitochondrial mass and sparing respiratory capacity (SRC) [201][202][203][204]. It has been recently shown that Opa-1 activity is essential to allow the correct formation and survival of T M cells, in which the mitochondrial network is clearly more elongated than in T E cells [202]. Pharmacological modulation of mitochondria-shaping proteins during in vitro T cell expansion, forcing mitochondria towards fusion, leads to the acquisition of a memory-like phenotype and to an increased survival rate, thus rendering T cells more effective in reducing tumor growth during adoptive cell immunotherapy (ACI) (Fig.…”

“…Once activated, the subtype of effector T cells (T E ) mainly rely on aerobic glycolysis to sustain their rapid proliferation rate [201]; this is achieved by fragmenting their mitochondrial network [202]. By contrast, memory T cells (T M ) switch towards fatty-acid oxidation to sustain their metabolism and self-renewal, thus increasing their mitochondrial mass and sparing respiratory capacity (SRC) [201][202][203][204]. It has been recently shown that Opa-1 activity is essential to allow the correct formation and survival of T M cells, in which the mitochondrial network is clearly more elongated than in T E cells [202].…”

Immunometabolism: Is it under the eye of the clock?

“…Metabolites such as succinate and citrate have a direct effect on the functioning of immune cells such as macrophages and dendritic cells [106]. Mitochondrial dynamics has been implicated as a major determinant in T-cell fate [107]. BMAL1 and the molecular clock are major players in immunity, metabolic reprogramming and mitochondrial homeostasis.…”

Reprogramming of metabolism in immune-mediated cells

“…Investigation of mitochondrial morphology demonstrated that memory T cells have fused mitochondria while effector T cells have fissed mitochondria. Fusion protein Opa1 is required for memory T cells [10].…”