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.
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Authors | Tiffany N Caza, David R Fernandez, Gergely Talaber, Zachary Oaks, Mark Haas, Michael P Madaio, Zhi-Wei Lai, Gabriella Miklossy, Ram R Singh, Dmitriy M Chudakov, Walter Malorni, Frank Middleton, Katalin Banki, Andras Perl |
Journal | Annals of the rheumatic diseases
(Ann Rheum Dis)
Vol. 73
Issue 10
Pg. 1888-97
(Oct 2014)
ISSN: 1468-2060 [Electronic] England |
PMID | 23897774
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. |
Chemical References |
- 2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid
- Diphosphonates
- Microtubule-Associated Proteins
- Mitochondrial Proteins
- Pyridines
- GTP Phosphohydrolases
- rab4 GTP-Binding Proteins
- DNM1L protein, human
- Dnm1l protein, mouse
- Dynamins
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Topics |
- Animals
- Autophagy
(physiology)
- Case-Control Studies
- Cells, Cultured
- Diphosphonates
(therapeutic use)
- Dynamins
(blood, physiology)
- Female
- GTP Phosphohydrolases
(blood, physiology)
- Homeostasis
(physiology)
- Humans
- Jurkat Cells
- Lupus Erythematosus, Systemic
(blood, drug therapy, immunology)
- Lysosomes
(metabolism)
- Mice, Inbred MRL lpr
- Microtubule-Associated Proteins
(blood, physiology)
- Mitochondria
(metabolism)
- Mitochondrial Proteins
(blood, physiology)
- Mitophagy
(immunology)
- Molecular Targeted Therapy
(methods)
- Pyridines
(therapeutic use)
- T-Lymphocytes
(metabolism)
- rab4 GTP-Binding Proteins
(physiology)
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