Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease

Abstract

Mitochondria has emerged as a critical ruler of metabolic reprogramming in immune responses and inflammation. In the context of colitogenic T cells and IBD, there has been increasing research interest in the metabolic pathways of glycolysis, pyruvate oxidation, and glutaminolysis. These pathways have been shown to play a crucial role in the metabolic reprogramming of colitogenic T cells, leading to increased inflammatory cytokine production and tissue damage. In addition to metabolic reprogramming, mitochondrial dysfunction has also been implicated in the pathogenesis of IBD. Studies have shown that colitogenic T cells exhibit impaired mitochondrial respiration, elevated levels of mROS, alterations in calcium homeostasis, impaired mitochondrial biogenesis, and aberrant mitochondria-associated membrane formation. Here, we discuss our current knowledge of the metabolic reprogramming and mitochondrial dysfunctions in colitogenic T cells, as well as the potential therapeutic applications for treating IBD with evidence from animal experiments.

Keywords: IBD - inflammatory bowel disease; T cell; immunometabolism; inflammation; mitochondria; treatment.

Figure 1

Metabolic Reprogramming and mitochondrial activity in CD4⁺ T subsets for pathogenesis of IBD. (A) Genetic susceptibility factors can trigger T cell-mediated immune dysregulation, leading to the onset of intestinal inflammation. (B) Pro-inflammatory CD4⁺ T cells become hyper-activated and demand metabolic reprogramming to meet their cellular needs for proliferation and effector functions. This metabolic shift involves the utilization of aerobic glycolysis, glutaminolysis, and mitochondrial oxidative respiration. (C) Regulatory T cells possess a higher number of healthy mitochondria that can efficiently utilize glucose oxidation to produce ATP without excess ROS generation. In contrast, pro-inflammatory Th17 cells rely on aerobic glycolysis and glutamine to fuel mitochondria and produce lactate. (D) Treg cells play a critical role in maintaining immune homeostasis in the gut mucosa by inhibiting immune responses. The imbalance between Treg and Th17 cells is a significant factor observed in patients with autoimmune diseases such as inflammatory bowel disease. Thus, targeting this imbalance could be an important strategy for the treatment of IBD.

Figure 2

Mitochondrial involvement in T cell activation and metabolic reprogramming during inflammation. T cell activation by T cell receptor with CD28 promotes metabolic reprogramming. CD28 activation leads to AKT and mTOR activation. Consequently, Hif1α and Myc transcription factors are upregulated, which accelerates aerobic glycolysis by increasing glucose uptake and lactate secretion to rapidly generate cellular ATP and carbon building blocks. Upon activation, pyruvate oxidation is decreased and glutaminolysis rather fuels TCA cycles in mitochondria in order to produce ATP. Glutamine is also rapidly consumed to process de novo nucleotide synthesis. Metabolic adaptation during T cell activation consequently leads to mitochondrial instability followed by mitochondrial ROS production, which can promote effector T cell polarization. Therefore, mitochondria is a pivot to all T cell metabolic reprogramming upon activation and differentiation. TCR, T cell receptor; GLUT, glucose transporter; AKT, protein kinase B; mTOR, mammalian target of rapamycin; TSC, tuberous sclerosis complex; LDHA, lactate dehydrogenase A; MPC, mitochondria pyruvate carrier; TCA, tricarboxylic acid cycle; OXPHOS, oxidative phosphorylation; AMPK, AMP-activated protein kinase.

Figure 3

Targeting T cell metabolic reprogramming for inflammation treatment. (A) Targeting general aerobic glycolysis drivers, such as mTOR, Myc, and Hif1a, with inhibitors like rapamycin, arctigenin, and 10058-F4, has demonstrated anti-inflammatory effects in autoimmune CD4⁺ T cells. Inhibiting the glucose transporter GLUT1 on the plasma membrane also restricts glycolysis, which slows T cell activation. Additionally, inhibiting HK2, the first glycolytic enzyme converting glucose to G6P, with 2-DG significantly decreases T cell activation. (B) Pyruvate oxidation can be enhanced by pyruvate supplementation. Inhibiting the MPC with compounds like UK5099 not only induces aerobic glycolysis by increasing pyruvate levels in the cytosol but also lowers mitochondrial calcium concentration, resulting in significant mitochondrial dysfunction in CD4⁺ T cells. Inhibiting PDHE1α with 1-AA alters mitochondrial pyruvate oxidation and can impact T cell development. Conversely, promoting pyruvate oxidation by inhibiting PDK with compounds like DCA, AZD7545, and GM10395 may be a potential therapeutic strategy for intestinal inflammation. Glut3 depletion reduces acetyl-CoA availability and histone acetylation (C) Glutaminolysis is associated with mitochondrial function and T cell activation. Glutamine serves as a source for de novo nucleotide synthesis during T cell activation and effector T cell polarization. Inhibiting de novo nucleotide synthesis with compounds like PALA and MPA or withdrawing glutamine with compounds like MSO or glutamine deprivation suppresses effector T cell polarization. Glutaminase inhibition with compounds like CB839, BPTES, and 968 leads to alterations in Th1/Th17 polarization and shows promise as a highly effective approach for inflammation treatment. TCR, T cell receptor; AKT, protein kinase B; TSC, tuberous sclerosis complex; mTOR, mammalian target of rapamycin; Hif1a, hypoxia-inducible factor 1; HK2, hexokinase 2; G6P, glucose-6-phosphate; GLUT1, glucose transporter 1; 2-DG, 2-dehydroxy-D-glucose; LDHA, lactate dehydrogenase A; MPC, mitochondria pyruvate carrier; PDK, pyruvate dehydrogenase kinase; LAT, Linker for activation of T cells; TCA, tricarboxylic acid cycle; PDP2, pyruvate dehydrogenase phosphatase 2; DCA, dichloroacetate; GS, glutamine synthetase;GLS, glutaminase; GSH, glutathione; PALA, N-(phosphonacetyl)-L-aspartate; MPA, mycophenolic acid; MSO, methionine sulfoximine; NAC, N-acetylcysteine; 2-HG, 2-Hydroxyglutarate; a-KG, alpha ketoglutarate; GDH, glutamate dehydrogenase; GPT, glutamate pyruvate transaminase; GOT, glutamate OAA transaminase; OAA, oxaloacetate.

Figure 4

Pyruvate oxidation disruption in hematopoietic stem cells and T cell progenitors alters normal T cell development. The metabolic alterations in hematopoietic stem cells and T cell progenitors can disrupt the normal development of T cells. During early hematopoietic development, pyruvate oxidation is not essential. The double deletion of PDK2/4 has no visible impact on long-term hematopoietic stem cells, but PDH inhibition (for example, with 1-AA) inhibits ST-HSC and MPP cells. Inhibiting MPC1 or PDHE1a, which results in the complete termination of pyruvate oxidation, can lead to severe mitochondrial dysfunction, affecting thymic selection and leading to the development of autoreactive T cells. MPC, mitochondria pyruvate carrier; LT-HSC, long term-hematopoietic stem cell; ST-HSC, short term-hematopoietic stem cell; DN, double negative cells; ISP, immature single-positive cells; DP, double positive cells; SP, single positive cells.

Figure 5

Mitochondrial biogenesis and morphology changes during T cell activation. (A) For T cell activation, it is necessary to undergo mitochondrial biogenesis to meet the energy requirements of the cell. When TFAM is inhibited, energy homeostasis is disrupted, and this results in the polarization of effector T cells. Additionally, PGC1a/TFAM activation is stimulated by IL-15, which leads to mitochondrial biogenesis. (B) The morphology of mitochondria in CD4⁺ T cells changes during TCR-mediated activation as time progresses. TCR, T cell receptor;PGC1a, peroxisome proliferator-activated receptor-gamma coactivator 1; NRF, Nuclear Respiratory Factor; TFAM, transcriptional factor A mitochondrial; OXPHOS, oxidative phosphorylation; ATP, Adenosine triphosphate; ROS, Reactive oxygen species; ARS, aminoacyl tRNA synthetase.

Figure 6

Targeting Mitochondrial Respiration Complexes for Modulating T Cell Activation and Inflammation. Activation of T cells results in upregulation of the TCA cycle and OXPHOS, which leads to the generation of oxidative stress. Inhibition of Complex V (such as oligomycin) hinders mitochondrial respiration and subsequently suppresses T cell activation and proliferation. Other mitochondrial respiratory complexes are also being explored as potential targets for drugs aimed at reducing T cell inflammation. TCR, T cell receptor; OXPHOS, oxidative phosphorylation; TCA cycle, tricarboxylic acid cycle;ROS, reactive oxygen species; CytC, Cytochrome C.

Figure 7

The role of mitochondrial calcium signaling and MAM in controlling T cell activation and differentiation. Under normal physiological conditions, mitochondria play a critical role in maintaining redox balance and energy metabolism by absorbing local calcium ions. However, during T cell activation, mitochondria take up cytosolic or ER calcium through the mitochondria-ER associated membrane contact site (MAM), which promotes TCA cycle, OXPHOS, and oxidative stress production. If mitochondrial calcium is depleted (e.g., using Ru360 or Ruthenium Red), or MAM formation is inhibited (e.g. using GM-10395, Xestospongin, VBIT-4, VBIT-12, nocodazole), it can suppress T cell activation, proliferation, and differentiation into effector T cells. ER, endoplasmic reticulum; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase;IP3R, inositol 1,4,5-trisphosphate receptor;HK, hexokinase;GRP75, glucose-regulated protein 75;PDK4, pyruvate dehydrogenase kinase 4; PDH, pyruvate dehydrogenase; MPC, mitochondria pyruvate carrier; VDAC, voltage-dependent anion channel; RyR, Ryanodine receptor; FCCP, Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; IDH, isocitrate dehydrogenase;KGDH, α-ketoglutarate dehydrogenase.