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.

• 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)
• 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

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)