Mitochondrial Dynamics Controls T Cell Fate Through Metabolic Programming

By Michael D. Buck, David O’Sullivan, R. K. Geltink, Jonathan D. Curtis, Chih-Hao Chang, David E Sanin, J. Qiu, O. Kretz, D. Braas, G. V. D. Windt and 9 more. Cell, 2016

1,283 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d402ed3382d5ead6e46d3e8cc04c016353e6dc5e

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Citations in the corpus

Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “After activation, CD8+ Te cells fragment their mitochondria in a process known as fission (71).”
Mitochondrial metabolism and cancer (2017, background): “At odds with their effector counterparts, memory T cells predominantly rely on fatty acid oxidation and OXPHOS to support their metabolic needs, a result of a metabolic reprogramming that involves not only mitochondrial elongation but also mechanistic target of rapamycin complex 1 (MTORC1) inhibitio”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “The changes can be detected by ultrastructural analysis: effector T cells have small distinct mitochondria, an indication of mitochondrial fission, whereas memory T cells have densely packed fused mitochondria (Buck et al., 2016).”
Mitochondrial dynamics in health and disease: mechanisms and potential targets (2023, background): “81 Once Drp1 is phosphorylated at Ser616, effector T cells exhibit higher mitochondrial ﬁ ssion frequency.”
Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances (2025, neutral): “216 The fusion of mitochondria was affected by OPA1, which can change mitochondrial inner membrane fusion.”
Metabolic Instruction of Immunity (2017, positive): “…by impairing glycolysis and boosting mitochondrial FAO and OXPHOS, metabolic pathways which favor the formation of resting memory T cell populations, potentiates effector T cell survival and functional capacity against tumors used in adoptive cell therapy (Buck et al., 2016; Sukumar et al., 2013).”
Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation (2018, background): “Activated effector T cells have punctate mitochondria and augmented the activity of anabolic pathways whereas memory T lymphocytes exhibit fused mitochondria and enhanced oxidative phosphorylation activity [138].”
Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis (2020, positive): “This obligates the cell to rely exclusively on oxidative phosphorylation (OXPHOS) for ATP generation (Aguer et al., 2011; Buck et al., 2016).”