HRES-1/Rab4-mediated depletion of Drp1 impairs mitochondrial homeostasis and represents a target for treatment in SLE

Abstract

Objective Accumulation of mitochondria underlies T-cell dysfunction in systemic lupus erythematosus (SLE). Mitochondrial turnover involves endosomal traffic regulated by HRES-1/Rab4, a small GTPase that is overexpressed in lupus T cells. Therefore, we investigated whether (1) HRES-1/Rab4 impacts mitochondrial homeostasis and (2) Rab geranylgeranyl transferase inhibitor 3-PEHPC blocks mitochondrial accumulation in T cells, autoimmunity and disease development in lupus-prone mice. Methods Mitochondria were evaluated in peripheral blood lymphocytes (PBL) of 38 SLE patients and 21 healthy controls and mouse models by flow cytometry, microscopy and western blot. MRL/lpr mice were treated with 125 μg/kg 3-PEHPC or 1 mg/kg rapamycin for 10 weeks, from 4 weeks of age. Disease was monitored by antinuclear antibody (ANA) production, proteinuria, and renal histology. Results Overexpression of HRES-1/Rab4 increased the mitochondrial mass of PBL (1.4-fold; p=0.019) and Jurkat cells (2-fold; p=0.000016) and depleted the mitophagy initiator protein Drp1 both in human (−49%; p=0.01) and mouse lymphocytes (−41%; p=0.03). Drp1 protein levels were profoundly diminished in PBL of SLE patients (−86±3%; p=0.012). T cells of 4-week-old MRL/lpr mice exhibited 4.7-fold over-expression of Rab4A (p=0.0002), the murine homologue of HRES-1/ Rab4, and depletion of Drp1 that preceded the accumulation of mitochondria, ANA production and nephritis. 3-PEHPC increased Drp1 (p=0.03) and reduced mitochondrial mass in T cells (p=0.02) and diminished ANA production (p=0.021), proteinuria (p=0.00004), and nephritis scores of lupus-prone mice (p<0.001). Conclusions These data reveal a pathogenic role for HRES-1/Rab4-mediated Drp1 depletion and identify endocytic control of mitophagy as a treatment target in SLE.

Increased Mitochondrial Electron Transport Chain Activity at Complex I Is Regulated byN-Acetylcysteine in Lymphocytes of Patients with Systemic Lupus Erythematosus

“…These findings are consistent with earlier observations that mitochondrial dysfunction of T cells is confined to patients with SLE relative to other rheumatic diseases (14,15,20). Here, we also confirm that NO is overproduced in patients with SLE (20), which is consistent with a role of NO in mitochondrial biogenesis (19,21,22) and increased mitochondrial mass in lupus T cells (4,11,20). NO production is also increased in lupus-prone mice, underlying its importance for lupus pathogenesis (23,31).…”

“…In turn, sustained exposure to NO triggers mitochondrial biogenesis (20,21). Thus, oxidative stress in SLE is associated with the accumulation of mitochondria that may be driven by increased NO-initiated biogenesis (20) and diminished mitophagy (4). While mitochondria are traditionally considered a primary source of energy production through oxidative phosphorylation, recent studies have clearly shown that they also regulate many signaling pathways, including T-cell activation and death pathway selection (10).…”

Autophagy is dispensable for B-cell development but essential for humoral autoimmune responses

“…[16][17][18] This deregulation could contribute to autoreactive T-cell survival and can be put in line with the deregulation of both macroautophagy and chaperone-mediated autophagy (CMA) in B cells that has been recently described to occur in lupus. 19,20 To date, however, these data remain correlative and no study has been published describing an in vivo model, prone to systemic autoimmunity, with specific autophagy deletion in B cells.…”

Pharmacological regulators of autophagy and their link with modulators of lupus disease

“…The authors did not evaluate the effects of TCR-related stimulation, which would have been particularly relevant on naïve T cells isolated from SLE patients. Two other studies also recently showed an increase of autophagic activity first, in peripheral blood lymphocytes from SLE patients and second, in CD4 T cells (Caza et al, 2014;Clarke et al, 2014). Thus, the question still remains open -is macroautophagy activity globally increased or decreased in lupus T cells?…”