Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

Abstract

T-cell activation, proliferation and selection of the cell death pathway depend on the production of reactive oxygen intermediates (ROIs) and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ). Mitochondrial hyperpolarization (MHP) and ATP depletion represent early and reversible steps in T-cell activation and apoptosis. By contrast, T cells of patients with systemic lupus erythematosus (SLE) exhibit persistent MHP, cytoplasmic alkalinization, increased ROI production and depleted ATP, which mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Necrotic, but not apoptotic, cell lysates activate dendritic cells and might account for increased interferon a production and inflammation in lupus patients. MHP is proposed as a key mechanism of SLE pathogenesis and is therefore a target for pharmacological intervention.Innate and adaptive immune responses depend on controlled production of ATP and reactive oxygen intermediates (ROIs) in mitochondria. In response to antigenic stimulation, clonal expansion of T and B cells are continuously downsized and potentially autoreactive cells are eliminated by apoptosis. An array of signals through the T-cell receptor (TCR), costimulatory molecules, cell death receptors, lymphokines, and other circulating metabolites, such as ATP, NAD, cADPR, glucose, glutathione, nitric oxide (NO) and ROIs, determine the fate of T cells [1]. T-cell activation and death pathway selection depend on the production of ROIs and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ) (Box 1). Disruption of ΔΨ m has been proposed as the point of no return in apoptotic signaling [2] T-cell activation is regulated by mitochondrial ROI productionROIs modulate T-cell activation, cytokine production and proliferation at multiple levels [12]. The antigen-binding αβ or γδTCR is associated with a multimeric receptor module comprising the CD3γδε and TCRζ chains. The cytoplasmic domains of the CD3 and ζ chains contain a common motif, termed the immunoreceptor tyrosinebased activation motif (ITAM), which is crucial for the coupling of intracellular tyrosine kinases [13]. . Thus, expression of cytokines can be selectively regulated by oxidative stress depending on the relative expression level of transcription factors involved (e.g. IL-2 is expressed through a promoter that has AP-1 and NFAT motifs, and IL-4 is expressed through an AP-1-less NFAT enhancer; Figure 1). Redox control of apoptosis signal processingProgrammed cell death (PCD) or apoptosis is a physiological mechanism for elimination of autoreactive lymphocytes during development. Signaling through the Fas or structurally related TNF family of cell-surface death receptors has emerged as a major pathway in the elimination of unwanted cells under physiological and disease conditions [18]. Fas and TNF receptors mediate cell death through cytoplasmic death domains (DDs) shared by both receptors [19]. They ...

Nuclear Poly(ADP-ribose) Polymerase-1 Rapidly Triggers Mitochondrial Dysfunction

“…(a) state 4 respiration (typically characterized by ADP deficiency); (b) Cyt-c oxidase dephosphorylation; and (c) F 1 F 0 inhibition (typically characterized by ADP accumulation) (48). Evidence that ADP contents were reduced by PARP-1 concomitant to ⌬⌿ m increase (Fig.…”

“…Such a bioenergetic state is likely because of PARP-1 activity-dependent neosynthesis of NAD from ATP, which prevents the latter from being re-transformed into ADP. Interestingly, PARP-1 activators, such as Fas, staurosporin, or H 2 O 2 , can increase ⌬⌿ m in intact cells (48). Further, the finding that Complex I is active and supports ⌬⌿ m during pyridine nucleotide depletion suggests that small amounts of NAD(H) suffice to provide electrons to counteract mitochondrial inner membrane proton leakage during PARP-1 hyperactivity.…”

Unique Dimeric Structure of BNip3 Transmembrane Domain Suggests Membrane Permeabilization as a Cell Death Trigger

“…Recently, homodimeric BNip3 was shown to induce ligand-dependent necrosis-like apoptosis in lymphocytes (12). The mitochondrial hyperpolarization was shown to be an essential early step of lymphocyte programmed death (47), and the identified conductive properties of BNip3 may prove important in this case.…”

Distinct Domains for Anti- and Pro-apoptotic Activities of IEX-1

“…A body of evidence indicates that ROS homeostasis is critical in maintaining mitochondrial membrane integrity (4,39,40). An acute increase in ROS production often causes irreversible damage of mitochondrial membrane integrity, leading to the release of cytochrome c and other proteins inside mitochondria (4,(7)(8)(9)(10)(11). Modulation of intracellular ROS production by IEX-1, in line with its association with mitochondria, explains multiple effects of IEX-1 on cellular responses to stress, because ROS can act as intracellular signaling molecules in a stress response in a variety of cell types, regulating apoptosis, proliferation, and transformation, besides a direct damage of mitochondrial membrane integrity.…”

“…The mitochondrial pathway triggers cell death as a consequence of alteration in mitochondrial membrane permeability induced by apoptotic effectors like oxidative stress and signaling-mediated translocation of Bax, Bad, Bid, or Bim, leading to the release of cytochrome c and other proteins contained in the mitochondrial intermembrane space (5,6). Substantial evidence indicates that prior to an irreparable loss of mitochondrial structural integrity, apoptotic effectors often stimulate an acute increase in the mitochondrial membrane potential ⌬ m that facilitates the formation of reactive oxygen species (ROS), 2 the amplitude of which determines a cell to die by apoptosis or to adapt (4,(7)(8)(9)(10)(11). Conceivably, prevention of ROS production in the initial phase of apoptosis is essential to guard the integrity of mitochondrial membrane, protecting cells from undergoing apoptosis.…”