Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia

Hypoxia is an important physiological stress that causes nerve injuries
and several brain diseases. However, the mechanism of brain response to
hypoxia remains unclear, thus limiting the development of interventional
strategies. This study conducted combined analyses of single-nucleus
transcriptome sequencing and extracellular vesicle transcriptome
sequencing on hypoxic mouse brains, described cell-cell communication in
the brain under hypoxia from intercellular and extracellular dimensions,
confirmed that hemoglobin mRNA was transferred from non-neuronal cells to
neurons, and eventually expressed. Then we further explored the role of
exosomal hemoglobin transfer in vitro, using human-derived cell lines, and
clarified that hypoxia promoted the transfer and expression of exosomal
hemoglobin between endothelial cells and neurons. And we found the vital
function of exosomal hemoglobin to protect against neurological injury by
maintaining mitochondrial homeostasis in neurons. In conclusion, this
study identified a novel mechanism of ‘mutual aid’ in hypoxia responses in
the brain, involving exosomal hemoglobin transfer, clarified the important
role of exosomal communication in the process of brain stress response,
and provided a novel interventional perspective for hypoxia-related brain
diseases.