The mitochondrial transmembrane potential (Δψm); negative inside and positive outside) is the result of an electrochemical gradient maintained by two transport systems – the electron transport chain and the F0F1-ATPase complex. The electron transport chain (ETC) catalyzes the flow of electrons from NADH to molecular oxygen and the translocation of protons across the inner mitochondrial membrane, thus creating a voltage gradient with negative charges inside the mitochondrial matrix. A small fraction of electrons react directly with oxygen and form reactive oxygen intermediates (ROIs). Activity of the F0F1-ATPase complex has crucial roles in oxidative phosphorylation (i.e. conversion of ADP to ATP at the expense of the electrochemical gradient during oxidative phosphorylation). Mitochondrial membrane integrity is dependent on the oxidation–reduction equilibrium of ROI, pyridine nucleotides (NADH/NAD þ NADPH/NADP) and reduced glutathione (GSH) levels. Regeneration of GSH by glutathione

reductase from its oxidized form, GSSG, depends on NADPH produced by the pentose phosphate pathway (PPP). ROI levels and Δψm are regulated by transaldolase through the supply of reducing equivalents from PPP, Ca2+ fluxing, and NO production. Whereas ROIs were long considered as toxic byproducts of aerobic existence, evidence has now accumulated that controlled levels of ROIs modulate various aspects of cellular function and are necessary for signal transduction pathways, including those mediating T-cell activation and death pathway selection. Mitochondrial hyperpolarization (MHP), an early event of T-cell activation and death, appears to be mediated through the inhibition of F0F1-ATPase (Banki et al). Nitric oxide (NO), acting as a competitive antagonist of oxygen, can also reversibly inhibit cytochrome c oxidase and cause MHP (Nagy et al). Using the energy of ATP, F0F1-ATPase can pump protons out of the mitochondrial matrix into the intermembrane space, thus causing Δψm elevation or MHP. MHP leads to uncoupling of oxidative phosphorylation (i.e. continued ROI production in the absence of ATP synthesis), which disrupts Δψm and damages integrity of the inner mitochondrial membrane. Disruption of Δψm has been proposed as the point of no return in apoptotic cell death signaling. This releases cytochrome c and other cell-death-inducing factors from mitochondria into the cytosol. Intracellular ATP concentration is a key switch in the decision of the cell to die by apoptosis or necrosis. Whereas apoptosis is energy dependent and persistent, MHP has been associated with ATP depletion and sensitization to necrosis in T cells of mice and patients with SLE. Thus, regulation of Δψm is a crucial checkpoint of T-cell fate decisions during developmental and pro-inflammatory lineage differentiation.

          MHP is caused by the inhibition of F0F1-ATPase by nitric oxide (Nagy et al.) and the blockade of electron transport at complex I due to the depletion of GSH in lupus T cells (Doherty at al.). Due the Rab4A-mediated depletion of mitophagy-initiator, dynamin-related protein 1 (Drp1), mitochondrial mass is increased in T cells of mice and patients with SLE (Caza et al; Talaber et al.)