Metabolic control of T cell activation and death in SLE

Abstract

Systemic lupus erythematosus (SLE) is characterized by abnormal T cell activation and death, processes which are crucially dependent on the controlled production of reactive oxygen intermediates (ROI) and of ATP in mitochondria. The mitochondrial transmembrane potential (Deltapsi(m)) has conclusively emerged as a critical checkpoint of ATP synthesis and cell death. Lupus T cells exhibit persistent elevation of Deltapsi(m) or mitochondrial hyperpolarization (MHP) as well as depletion of ATP and glutathione which decrease activation-induced apoptosis and instead predispose T cells for necrosis, thus stimulating inflammation in SLE. NO-induced mitochondrial biogenesis in normal T cells accelerates the rapid phase and reduces the plateau of Ca(2+) influx upon CD3/CD28 co-stimulation, thus mimicking the Ca(2+) signaling profile of lupus T cells. Treatment of SLE patients with rapamycin improves disease activity, normalizes CD3/CD28-induced Ca(2+) fluxing but fails to affect MHP, suggesting that altered Ca(2+) fluxing is downstream or independent of mitochondrial dysfunction. Understanding the molecular basis and consequences of MHP is essential for controlling T cell activation and death signaling in SLE.

Fig 1

A) Schematic outline of the metabolic pathways controlling (PPP,GSH, NO) and sensing (mTOR) mitochondrial hyperpolarization (MHP) of lupus T cells. In normal T cells, MHP and mitochondrial biogenesis is mediated via production of NO by eNOS or nNOS (28)and up-regulation of transcription factors PGC-1α, Tfam, and ALAS (39). NO production by eNOS may be compartmentalized to the T cell synapse (29). NO causes transient MHP via reversible inhibition of complex IV/cytochrome c oxidase (7) and persistent MHP via S-nitrosylation of complex I of the ETC in a state of GSH depletion (24). The PPP regulates the Δψ_m by producing 1) NADPH that serves as a reducing equivalent for GSH regeneration from its oxidized form GSSG and for production of NO by NOS and 2) ribose 5-phosphate for biosynthesis of nucleotides, ADP, ATP, NAD, NAADP, (c)ADP-ribose, and cGMP, the latter is a second messenger of NO. NAADP and (c) ADP-ribose induce Ca²⁺ release from the endoplasmic reticulum (ER) via ryanodine receptors (RyR). mTOR senses Δψ_m and regulates IP3R-mediated Ca²⁺ release (40). The intracellular rapamycin receptor FKBP12 directly binds the RyR. The Bcl-2 family proteins control permeability of the outer mitochondrial membrane and release of apoptosis-inducing factors. Necrosis-prone T cells release oxidized DNA and HMGB1 which stimulate B cells, macrophages, and dendritic cells (DC). In turn, B cells produce IL-10 and macrophages and DC produce NO which stimulate MHP of T cells. B) Proposed hierarchy of metabolic pathways upstream and downstream of MHP in lupus T cells. Broken line demarcates checkpoints affected by rapamycin.