Your browser doesn't support javascript.
loading
A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease.
Bharat, Vinita; Durairaj, Aarooran S; Vanhauwaert, Roeland; Li, Li; Muir, Colin M; Chandra, Sujyoti; Kwak, Chulhwan S; Le Guen, Yann; Nandakishore, Pawan; Hsieh, Chung-Han; Rensi, Stefano E; Altman, Russ B; Greicius, Michael D; Feng, Liang; Wang, Xinnan.
Afiliación
  • Bharat V; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Durairaj AS; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Vanhauwaert R; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Li L; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Muir CM; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Graduate Program of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Chandra S; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Kwak CS; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Le Guen Y; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Institut du Cerveau - Paris Brain Institute - ICM, 75013 Paris, France.
  • Nandakishore P; Vroom Inc., Houston, TX 77042, USA.
  • Hsieh CH; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Rensi SE; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • Altman RB; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • Greicius MD; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Feng L; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Wang X; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: xinnanw@stanford.edu.
Cell Rep ; 42(12): 113544, 2023 12 26.
Article en En | MEDLINE | ID: mdl-38060381
ABSTRACT
Dysregulated iron or Ca2+ homeostasis has been reported in Parkinson's disease (PD) models. Here, we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca2+ overflow, through an interaction of Fe2+ with mitochondrial calcium uniporter (MCU). In PD neurons, iron accumulation-triggered Ca2+ influx across the mitochondrial surface leads to spatially confined Ca2+ elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca2+-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover Food and Drug Administration-approved T-type Ca2+-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca2+-channel subtypes associated with PD status. Our results identify a molecular mechanism in PD pathophysiology and drug targets and candidates coupled with a convenient stratification method.
Asunto(s)
Palabras clave
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Calcio Límite: Humans Idioma: En Revista: Cell Rep Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Calcio Límite: Humans Idioma: En Revista: Cell Rep Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos