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Extended report
HRES-1/Rab4-mediated depletion of Drp1 impairs mitochondrial homeostasis and represents a target for treatment in SLE
  1. Tiffany N Caza1,
  2. David R Fernandez1,
  3. Gergely Talaber1,
  4. Zachary Oaks1,
  5. Mark Haas2,
  6. Michael P Madaio3,
  7. Zhi-wei Lai1,
  8. Gabriella Miklossy1,
  9. Ram R Singh4,
  10. Dmitriy M Chudakov5,
  11. Walter Malorni6,
  12. Frank Middleton1,
  13. Katalin Banki1,
  14. Andras Perl1
  1. 1Departments of Medicine, Microbiology, and Immunology, Biochemistry and Molecular Biology, Neuroscience and Physiology, and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA
  2. 2Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA
  3. 3Department of Medicine, Medical College of Georgia, Augusta, Georgia, USA
  4. 4Department of Medicine, UCLA, Los Angeles, California, USA
  5. 5Shemiakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russia
  6. 6Department of Experimental Medicine, University of Rome, Rome, Italy
  1. Correspondence to Dr Andras Perl, Department of Medicine, State University of New York, 750 East Adams Street, Syracuse, New York 13210, USA; perla{at}upstate.edu

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.

  • Autoimmune Diseases
  • Autoimmunity
  • Systemic Lupus Erythematosus

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