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

Area of Science:

• Neuroscience
• Immunology
• Mitochondrial Biology

Background:

• Primary mitochondrial diseases (PMDs) often involve neurological disorders linked to oxidative phosphorylation (OXPHOS) defects.
• Gliosis and symptom amelioration via microglial depletion in PMD models suggest a role for these brain immune cells.

Purpose of the Study:

• To investigate if OXPHOS deficits specifically in microglia contribute to the pathology of PMDs.
• To understand the role of mitochondrial Complex I (CI) in microglial function and its impact on neurological health.

Main Methods:

• In vitro studies assessing microglial metabolic response to stimulation and CI inhibition (rotenone).
• Generation and analysis of a mouse model with CI deficiency specifically in microglia (MGcCI).
• Assessment of microglial morphology, gene expression, brain pathology (gliosis, synaptic markers), and behavioral deficits in MGcCI mice.

Main Results:

• Microglial stimulation showed altered metabolic rewiring with CI inhibition in vitro.
• MGcCI mice exhibited microglial metabolic and transcriptional changes, leading to hypertrophy and dysfunction.
• MGcCI mice displayed reactive astrocytes, synaptic loss, altered neuronal populations, behavioral deficits, and premature death, partially rescued by microglial depletion.

Conclusions:

• Microglial development and function are dependent on mitochondrial Complex I activity.
• OXPHOS deficits in microglia represent a direct contribution to primary mitochondrial diseases, offering new therapeutic avenues.