2. Academic Validation
  3. Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis

Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis

  • Cell Death Dis. 2023 Nov 25;14(11):772. doi: 10.1038/s41419-023-06290-1.
Alejandro Marmolejo-Garza # 1 2,  Inge E Krabbendam # 1,  Minh Danh Anh Luu 1,  Famke Brouwer 1,  Marina Trombetta-Lima 1 2,  Osman Unal 1,  Shane J O'Connor 1,  Naďa Majerníková 3,  Carolina R S Elzinga 1,  Cristina Mammucari 4,  Martina Schmidt 1,  Muniswamy Madesh 5,  Erik Boddeke 2,  Amalia M Dolga 6
Affiliations

Affiliations

  • 1 Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands.
  • 2 Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • 3 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • 4 Department of Biomedical Sciences, University of Padua, 35131, Padua, Italy.
  • 5 Department of Medicine/Cardiology, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • 6 Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands. a.m.dolga@rug.nl.
  • # Contributed equally.
PMID: 38007529 DOI: 10.1038/s41419-023-06290-1
Abstract

Ferroptosis is an iron- and Reactive Oxygen Species (ROS)-dependent form of regulated cell death, that has been implicated in Alzheimer's disease and Parkinson's disease. Inhibition of cystine/glutamate antiporter could lead to mitochondrial fragmentation, mitochondrial calcium ([CA2+]m) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨm), and ferroptotic cell death. The observation that mitochondrial dysfunction is a characteristic of Ferroptosis makes preservation of mitochondrial function a potential therapeutic option for diseases associated with ferroptotic cell death. Mitochondrial calcium levels are controlled via the mitochondrial calcium uniporter (MCU), the main entry point of CA2+ into the mitochondrial matrix. Therefore, we have hypothesized that negative modulation of MCU complex may confer protection against Ferroptosis. Here we evaluated whether the known negative modulators of MCU complex, ruthenium red (RR), its derivative Ru265, mitoxantrone (MX), and MCU-i4 can prevent mitochondrial dysfunction and ferroptotic cell death. These compounds mediated protection in HT22 cells, in human dopaminergic neurons and mouse primary cortical neurons against ferroptotic cell death. Depletion of MICU1, a [CA2+]m gatekeeper, demonstrated that MICU is protective against Ferroptosis. Taken together, our results reveal that negative modulation of MCU complex represents a therapeutic option to prevent degenerative conditions, in which Ferroptosis is central to the progression of these pathologies.

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