Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration

Guangyan Miao; Tina M Fortier; Haibo Liu; Dorothy P Schafer; Katherine A Fitzgerald; Junhao Mao; Eric H Baehrecke

doi:10.1038/s41594-025-01602-9

Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration

Nat Struct Mol Biol. 2025 Jun 25. doi: 10.1038/s41594-025-01602-9. Online ahead of print.

Authors

Guangyan Miao¹, Tina M Fortier¹, Haibo Liu¹, Dorothy P Schafer², Katherine A Fitzgerald³, Junhao Mao¹, Eric H Baehrecke⁴

Affiliations

¹ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
² Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
³ Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
⁴ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA. eric.baehrecke@umassmed.edu.

PMID: 40563011
DOI: 10.1038/s41594-025-01602-9

Abstract

The failure to clear dysfunctional mitochondria, cell death and inflammation have been linked in neurodegenerative disease, but their relationship and role in these conditions is not fully understood. Loss of Vps13d prevents clearance of mitochondria, and mutations in human VPS13D have been associated with neurological movement disorders. To investigate the relationship between mitochondrial health, inflammation and neurodegeneration, we created a conditional Vps13d-knockout mouse. Loss of Vps13d in excitatory neurons resulted in behavioral changes and neurodegeneration. Vacuolar protein sorting 13D (VPS13D) deficiency also caused mitochondrial ultrastructural defects and dysfunction in neurons followed by gasdermin E processing, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon response cGAMP interactor (STING) signaling, microglial activation and cell death. Gasdermin E localization with mitochondria in Vps13d-mutant neurons was required for elevated extracellular mitochondrial DNA that promoted activation of microglia. Depletion of microglia suppressed cell death and behavioral phenotypes but not mitochondrial changes in the neuron-specific Vps13d-knockout model, indicating that microglia promote cell death in this model of neurodegenerative disease.