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

• Published in: Annals of the rheumatic diseases Vol. 73; no. 10; pp. 1888 - 1897
• Main Authors: Caza, Tiffany N, Fernandez, David R, Talaber, Gergely, Oaks, Zachary, Haas, Mark, Madaio, Michael P, Lai, Zhi-wei, Miklossy, Gabriella, Singh, Ram R, Chudakov, Dmitriy M, Malorni, Walter, Middleton, Frank, Banki, Katalin, Perl, Andras
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01.10.2014; BMJ Publishing Group
• Series: Extended report
• Subjects: Animals; Antigens; Autophagy; Autophagy - physiology; Basic and Translational Research; Blood & organ donations; Case-Control Studies; Cells, Cultured; Diphosphonates - therapeutic use; Dynamins - blood; Dynamins - physiology; Female; Fibroblasts; Gene expression; GTP Phosphohydrolases - blood; GTP Phosphohydrolases - physiology; Homeostasis; Homeostasis - physiology; Humans; Immunoglobulins; Jurkat Cells; Lupus; Lupus Erythematosus, Systemic - blood; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - immunology; Lymphocytes; Lysosomes - metabolism; Mice, Inbred MRL lpr; Microtubule-Associated Proteins - blood; Microtubule-Associated Proteins - physiology; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - blood; Mitochondrial Proteins - physiology; Mitophagy - immunology; Molecular Targeted Therapy - methods; Pathogenesis; Proteins; Pyridines - therapeutic use; rab4 GTP-Binding Proteins - physiology; T cell receptors; T-Lymphocytes - metabolism; Autoimmunity; Systemic Lupus Erythematosus; Autoimmune Diseases
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/annrheumdis-2013-203794

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.