title: 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.affiliation: Departments of Medicine, Microbiology, and Immunology, Biochemistry and Molecular Biology, Neuroscience and Physiology, and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Tiffany N
authors.initials: TN
authors.lastname: Caza
authors.affiliation: Departments of Medicine, Microbiology, and Immunology, Biochemistry and Molecular Biology, Neuroscience and Physiology, and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Fernandez
authors.affiliation: Departments of Medicine, Microbiology, and Immunology, Biochemistry and Molecular Biology, Neuroscience and Physiology, and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Gergely
authors.initials: G
authors.lastname: Talaber
authors.affiliation: Departments of Medicine, Microbiology, and Immunology, Biochemistry and Molecular Biology, Neuroscience and Physiology, and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Oaks
authors.affiliation: Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Haas
authors.affiliation: Department of Medicine, Medical College of Georgia, Augusta, Georgia, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Madaio
authors.affiliation: Departments of Medicine, Microbiology, and Immunology, Biochemistry and Molecular Biology, Neuroscience and Physiology, and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Lai
authors.affiliation: Departments of Medicine, Microbiology, and Immunology, Biochemistry and Molecular Biology, Neuroscience and Physiology, and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Miklossy
authors.affiliation: Department of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Ram R
authors.initials: RR
authors.lastname: Singh
authors.affiliation: Shemiakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russia.
authors.forename: Dmitriy M
authors.initials: DM
authors.lastname: Chudakov
authors.affiliation: Department of Experimental Medicine, University of Rome, Rome, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
authors.affiliation: Departments of Medicine, Microbiology, and Immunology, Biochemistry and Molecular Biology, Neuroscience and Physiology, and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Middleton
authors.affiliation: Departments of Medicine, Microbiology, and Immunology, Biochemistry and Molecular Biology, Neuroscience and Physiology, and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Banki
authors.affiliation: Departments of Medicine, Microbiology, and Immunology, Biochemistry and Molecular Biology, Neuroscience and Physiology, and Pathology, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Andras
authors.initials: A
authors.lastname: Perl
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004164:Diphosphonates / Q000627:therapeutic use; D034281:Dynamins / Q000097:blood / Q000502:physiology; D005260:Female; D020558:GTP Phosphohydrolases / Q000097:blood* / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000188:drug therapy / Q000276:immunology; D008247:Lysosomes / Q000378:metabolism; D019463:Mice, Inbred MRL lpr; D008869:Microtubule-Associated Proteins / Q000097:blood* / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000097:blood* / Q000502:physiology; D063306:Mitophagy / Q000276:immunology; D058990:Molecular Targeted Therapy / Q000379:methods; D011725:Pyridines / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000378:metabolism; D020695:rab4 GTP-Binding Proteins / Q000502:physiology*
chemical_list: C410028:2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid; D004164:Diphosphonates; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011725:Pyridines; D020558:GTP Phosphohydrolases; D020695:rab4 GTP-Binding Proteins; C110768:DNM1L protein, human; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: Autoimmune Diseases; Autoimmunity; Systemic Lupus Erythematosus
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