Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia
Curation statements for this article:-
Curated by eLife
eLife Assessment
This valuable paper seeks to determine the role of endogenous CNS hemoglobin in protecting mitochondrial homeostasis in hypoxia. There is merit in the work, although it remains incomplete as there is a question as to the validity of the hypoxia model as relevant to CNS-specific ischemia/hypoxia that should be considered. In particular, a whole-body hypoxia model may liberate exosomes from other hypoxic organs, which should be addressed by the authors. Overall, this work has the potential to be of broad interest to the neuroscience and hypoxia communities.
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Abstract
Hypoxia is an important physiological stress causing 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 , 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.
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eLife Assessment
This valuable paper seeks to determine the role of endogenous CNS hemoglobin in protecting mitochondrial homeostasis in hypoxia. There is merit in the work, although it remains incomplete as there is a question as to the validity of the hypoxia model as relevant to CNS-specific ischemia/hypoxia that should be considered. In particular, a whole-body hypoxia model may liberate exosomes from other hypoxic organs, which should be addressed by the authors. Overall, this work has the potential to be of broad interest to the neuroscience and hypoxia communities.
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Reviewer #1 (Public Review):
Summary:
This study investigates the hypoxia rescue mechanisms of neurons by non-neuronal cells in the brain from the perspective of exosomal communication between brain cells. Through multi-omics combined analysis, the authors revealed this phenomenon and logically validated this intercellular rescue mechanism under hypoxic conditions through experiments. The study proposed a novel finding that hemoglobin maintains mitochondrial function, expanding the conventional understanding of hemoglobin. This research is highly innovative, providing new insights for the treatment of hypoxic encephalopathy.
Overall, the manuscript is well organized and written, however, there are some minor/major points that need to be revised before this manuscript is accepted.
Major points:
(1) Hypoxia can induce endothelial cells to …
Reviewer #1 (Public Review):
Summary:
This study investigates the hypoxia rescue mechanisms of neurons by non-neuronal cells in the brain from the perspective of exosomal communication between brain cells. Through multi-omics combined analysis, the authors revealed this phenomenon and logically validated this intercellular rescue mechanism under hypoxic conditions through experiments. The study proposed a novel finding that hemoglobin maintains mitochondrial function, expanding the conventional understanding of hemoglobin. This research is highly innovative, providing new insights for the treatment of hypoxic encephalopathy.
Overall, the manuscript is well organized and written, however, there are some minor/major points that need to be revised before this manuscript is accepted.
Major points:
(1) Hypoxia can induce endothelial cells to release exosomes carrying hemoglobin, however, how neurons are able to actively take up these exosomes? It is possible for other cells to take up these exosomes also? This point needs to be clarified in this study.
(2) The expression of hemoglobin in neurons is important for mitochondrial homeostasis, but its relationship with mitochondrial homeostasis needs to be further elucidated in the study.
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Reviewer #2 (Public Review):
Summary:
This is an interesting study with a lot of data. Some of these ideas are intriguing. But a few major points require further consideration.
Major points:
(1) What disease is this model of whole animal hypoxia supposed to mimic? If one is focused on the brain, can one just use a model of focal or global cerebral ischemia?
(2) If this model subjects the entire animal to hypoxia, then other organs will also be hypoxic. Should one also detect endothelial upregulation and release of extracellular vesicles containing hemoglobin mRNA in non-CNS organs? Where do these vesicles go? Into blood?
(3) What other mRNA are contained in the vesicles released from brain endothelial cells?
(4) Where do the endothelial vesicles go? Only to neurons? Or to other cells as well?
(5) Neurons can express endogenous …
Reviewer #2 (Public Review):
Summary:
This is an interesting study with a lot of data. Some of these ideas are intriguing. But a few major points require further consideration.
Major points:
(1) What disease is this model of whole animal hypoxia supposed to mimic? If one is focused on the brain, can one just use a model of focal or global cerebral ischemia?
(2) If this model subjects the entire animal to hypoxia, then other organs will also be hypoxic. Should one also detect endothelial upregulation and release of extracellular vesicles containing hemoglobin mRNA in non-CNS organs? Where do these vesicles go? Into blood?
(3) What other mRNA are contained in the vesicles released from brain endothelial cells?
(4) Where do the endothelial vesicles go? Only to neurons? Or to other cells as well?
(5) Neurons can express endogenous hemoglobin. Is it useful to subject neurons to hypoxia and then see how much the endogenous mRNA goes up? How large is the magnitude of endogenous hemoglobin gene upregulation compared to the hypothesized exogenous mRNA that is supposed to be donated from endothelial vesicles?
(6) Finally, it may be useful to provide more information and data to explain how the expression of this exogenous endothelial-derived hemoglobin binds to neuronal mitochondria to alter function.
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