https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00486-3
Sadly again behind a paywall. What I find interesting here is that mitochondria from outside the CNS are getting into the CNS.
Highlights
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Excessive vigorous exercise causes cognitive impairment
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ATF5 lactylation promotes the secretion of otMDVs during excessive vigorous exercise
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otMDVs are characterized by enriched surface marker PAF and content mtDNA
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otMDVs induce synaptic energy deficits by occupying mitochondrial anchor sites
Summary
Excessive exercise impairs cognitive function, but the underlying mechanism remains unclear. Here, we show that excessive vigorous exercise-induced lactate accumulation stimulates muscles to secrete mitochondria-derived vesicles (MDVs), driving cognitive impairment. These MDVs (named otMDVs) are characterized by high mtDNA levels and the surface marker PAF. They tend to migrate into hippocampal neurons, substituting endogenous mitochondria and triggering a synaptic energy crisis. Mechanistically, otMDVs release mtDNA, which activates cGAS-STING-dependent inhibition of kinesin family member 5, preventing hippocampal mitochondria from transporting to synapses. Simultaneously, the otMDV marker PAF cooperates with syntaphilin to occupy mitochondrial anchoring sites, impairing synaptic energy supply. Blocking otMDVs migration into the hippocampus with a PAF-neutralizing antibody alleviates excessive vigorous exercise-induced synapse loss and cognitive dysfunction. Notably, human studies link high circulating otMDV levels to cognitive impairment. Together, our findings reveal that a unique muscle-derived MDV subpopulation, which displaces hippocampal mitochondria and disrupts their function, causes cognitive decline.