2. Academic Validation
  3. Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality

Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality

  • Nat Metab. 2024 Aug;6(8):1479-1491. doi: 10.1038/s42255-024-01081-0.
Bella Mora-Romero # 1 2 3,  Nicolas Capelo-Carrasco # 1 3 4,  Juan J Pérez-Moreno # 5 6 7,  María I Alvarez-Vergara 1 2 3 8,  Laura Trujillo-Estrada 3 9,  Carmen Romero-Molina 1 3 4 10,  Emilio Martinez-Marquez 1 3 11,  Noelia Morano-Catalan 1 3,  Marisa Vizuete 1 3 4,  Jose Lopez-Barneo 1 3 11,  Jose L Nieto-Gonzalez 1 3 11,  Pablo Garcia-Junco-Clemente 1 3 11,  Javier Vitorica 1 3 4,  Antonia Gutierrez 3 9,  David Macias 1 11,  Alicia E Rosales-Nieves 1 3 4,  Alberto Pascual 12 13
Affiliations

Affiliations

  • 1 Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
  • 2 Department of Biología Celular, Facultad de Biología, Universidad de Sevilla, Seville, Spain.
  • 3 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
  • 4 Department of Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain.
  • 5 Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. jpmoreno@us.es.
  • 6 Department of Biología Celular, Facultad de Biología, Universidad de Sevilla, Seville, Spain. jpmoreno@us.es.
  • 7 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. jpmoreno@us.es.
  • 8 Institute for Neurovascular Cell Biology, University Hospital Bonn, Bonn, Germany.
  • 9 Department of Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigacion Biomedica de Malaga (IBIMA), Universidad de Málaga, Málaga, Spain.
  • 10 Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11 Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain.
  • 12 Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. apascual-ibis@us.es.
  • 13 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. apascual-ibis@us.es.
  • # Contributed equally.
PMID: 39048800 DOI: 10.1038/s42255-024-01081-0
Abstract

Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to Oxidative Phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.

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