Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.

Summary

Excessive vigorous exercise elevates lactate, triggering muscle secretion of mitochondria-derived vesicles (otMDVs) that enter hippocampal neurons, displace endogenous mitochondria, and impair synaptic energetics via cGAS–STING–KIF5 inhibition and PAF–syntaphilin–mediated anchoring disruption. A PAF-neutralizing antibody mitigated synapse loss and cognitive deficits; human data linked higher circulating otMDVs with cognitive impairment.

Key Findings

• Lactate from excessive vigorous exercise induces muscle secretion of mitochondria-derived vesicles (otMDVs) with high mtDNA and PAF marker.
• otMDVs traffic to hippocampal neurons, replace endogenous mitochondria, and cause synaptic energy crisis.
• Released mtDNA activates cGAS–STING, inhibiting KIF5-dependent mitochondrial transport; PAF cooperates with syntaphilin to block mitochondrial anchoring.
• PAF-neutralizing antibody prevents otMDV hippocampal entry and ameliorates synapse loss and cognitive impairment; human association corroborated.

Clinical Implications

Supports avoiding overtraining in at-risk individuals and motivates development of biomarkers (circulating otMDVs/PAF) and targeted interventions (e.g., PAF blockade) to protect cognition.

Limitations

• Rodent exercise paradigms may not fully reflect human training patterns and thresholds.
• Translatability of PAF as a therapeutic target and safety of long-term blockade remain to be established.

Future Directions

Define dose–response thresholds for otMDV induction in humans, develop clinical assays for circulating otMDVs/PAF, and test targeted interventions (PAF or cGAS–STING modulation) in controlled trials.