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Stroke. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: Stroke. 2016 November ; 47(11): e250–e251. doi:10.1161/STROKEAHA.116.015181.
Stroke Literature Synopses: Basic Science (2016/Sep) Ken Arai Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, USA.
Author Manuscript
The mitochondrion is the major organelle responsible for energy generation in order to maintain cellular homeostasis. Mitochondrial dysfunction is observed in many CNS diseases including stroke. Three recent studies summarized below provide novel insights into mitochondrial mechanisms that may impact neuronal function.
Author Manuscript
Wang et al (The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nature Medicine. 2016;32:869–878) revealed that mitochondrial localization of TAR DNA-binding protein 43 (TDP-43) in neurons caused mitochondrial dysfunction to induce neuronal death, and proposed that TDP-43 mitochondrial localization can be a therapeutic target for neurodegeneration. TDP-43 is an RNA- and DNA-binding protein. Previous studies implied that the redistribution of TDP-43 from the nucleus to cytoplasm is closely related to degenerating neurons in CNS diseases, such as amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). To examine the underlying molecular mechanisms, the authors first investigated the co-localization of TDP-43 with neuronal organelles in CNS samples from ALS and FTD patients. Compared to the control cases, ALS motor neurons and FTD cortical neurons exhibited high levels of cytoplasmic TDP-43 accumulation, and the cytoplasmic TDP-43 was co-localized with mitochondrial markers. In addition, cell-free and cell-culture experiments confirmed that disease-associated mutations of TDP-43 increased the mitochondrial localization of TDP-43, and TDP-43 in mitochondria reduced the synthesis of ND3 and ND6, which impaired mitochondrial oxidative phosphorylation complex I. Finally, the authors demonstrated that mice that received neuron-specific bicistronic lentiviruses encoding disease-associate mutant of TDP-43 exhibited mitochondrial fragmentation along with neuronal death. Because similar energetic perturbations occur in ischemic mitochondria, this study provides a basis for generating hypotheses for investigating analogous TDP-43 pathways in the context of stroke.
Author Manuscript
Neuronal mitochondria play important roles in maintaining neuronal function and survival in a cell-autonomous fashion (e.g. via intracellular mechanisms). However, mitochondria in other types of cells may also contribute to impact neuronal function under diseased conditions. Chikka et al (The Mitochondria-Regulated Immune Pathway Activated in the C. elegans Intestine Is Neuroprotective. Cell Reports. 2016;16:1–6) showed that mitochondrial dysfunction in intestinal cells would activate immune pathways, which acts as neuroprotective. The authors exposed c. elegans to the mitotoxin rotenone stimulation as a
Corresponding author: Ken Arai, Ph.D., Neuroprotection Research Laboratory, MGH East 149-2401, Charlestown, MA 02129, USA. Tel: 617.724.9503, [email protected].
Arai
Page 2
Author Manuscript Author Manuscript
model system of neurodegenerative disorders. Upon rotenon exposure, p38MAPK/ATF-7 signaling in intestinal cells was activated due to mitochondrial complex I dysfunction. Overexpression of p38MAPK only in the gut increased ATF-7 target gene expression upon rotenone exposure compared to controls, which resulted in suppressing rotenone-induced dopaminergic neuron degeneration. Also, overexpression of inactive p38MAPK in the gut exhibited dopaminergic neuronal damage by rotenone exposure. For the underlying mechanisms, the authors demonstrated that P38MAPK/ATF-7 activation decreased oxidative damage through the removal of dysfunctional mitochondria by mirochondrial autophagy (e.g. mitophagy). Taken together, these data suggest that mitochondria in intestinal cells may protect neurons in a non-cell-autonomous fashion under diseased conditions. An emerging literature now points to the importance of crosstalk between the gut and post-stroke inflammation that may be mediated by the microbiome. This study suggests that mitochondrial responses may also be involved in these critical pathways of centralperipheral crosstalk.
Author Manuscript
Hayakawa et al (Transfer of mitochondria from astrocytes to neurons after stroke. Nature;535:551–555) proposes that non-cell autonomous signaling within the neurovascular unit may also involve the exchange of mitochondria. In this study, astrocytes may actively release functional mitochondria via calcium-dependent mechanisms, and neighboring neurons that incorporated those astrocyte-derived mitochondria became more resistant to ischemic stress. The authors first conducted cell culture experiments to confirm the existence of functional mitochondria in astrocyte-conditioned culture media. They also showed that astrocyte-derived mitochondria-contained culture media indeed protected neurons against oxygen-glucose deprivation. In addition, cultured neurons absorbed astrocyte-derived mitochondia under the stressed conditions, and this mitochondria transfer was mediated via CD38/cyclic-ADP signaling in astrocytes because siRNA suppression of CD38 in astrocytes reduced the transfer in the astrocyte-neuron co-culture system. Correspondingly, in an in vivo mouse model of transient focal ischemia, neurons in periinfarct areas appeared to contain astrocyte-derived mitochondria. Furthermore, CD38suppression by siRNA decreased the mitochondria transfer from astrocytes to neurons and worsened the neurological deficits without affecting the number of CD38-expressing immune cells in brain. These data implied that under diseased conditions, mitochondria may travel from astrocytes to neurons as part of an endogenous program to protect and support neurons at risk.
Author Manuscript
These three new studies all demonstrate the central role of novel mitochondrial mechanisms that may help regulate neuronal function under diseased conditions. Further investigations are warranted to determine whether and how these mechanisms may be leveraged or targeted for improving outcomes in stroke patient.
Stroke. Author manuscript; available in PMC 2017 November 01.
Stroke. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: Stroke. 2016 November ; 47(11): e250–e251. doi:10.1161/STROKEAHA.116.015181.
Stroke Literature Synopses: Basic Science (2016/Sep) Ken Arai Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, USA.
Author Manuscript
The mitochondrion is the major organelle responsible for energy generation in order to maintain cellular homeostasis. Mitochondrial dysfunction is observed in many CNS diseases including stroke. Three recent studies summarized below provide novel insights into mitochondrial mechanisms that may impact neuronal function.
Author Manuscript
Wang et al (The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nature Medicine. 2016;32:869–878) revealed that mitochondrial localization of TAR DNA-binding protein 43 (TDP-43) in neurons caused mitochondrial dysfunction to induce neuronal death, and proposed that TDP-43 mitochondrial localization can be a therapeutic target for neurodegeneration. TDP-43 is an RNA- and DNA-binding protein. Previous studies implied that the redistribution of TDP-43 from the nucleus to cytoplasm is closely related to degenerating neurons in CNS diseases, such as amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). To examine the underlying molecular mechanisms, the authors first investigated the co-localization of TDP-43 with neuronal organelles in CNS samples from ALS and FTD patients. Compared to the control cases, ALS motor neurons and FTD cortical neurons exhibited high levels of cytoplasmic TDP-43 accumulation, and the cytoplasmic TDP-43 was co-localized with mitochondrial markers. In addition, cell-free and cell-culture experiments confirmed that disease-associated mutations of TDP-43 increased the mitochondrial localization of TDP-43, and TDP-43 in mitochondria reduced the synthesis of ND3 and ND6, which impaired mitochondrial oxidative phosphorylation complex I. Finally, the authors demonstrated that mice that received neuron-specific bicistronic lentiviruses encoding disease-associate mutant of TDP-43 exhibited mitochondrial fragmentation along with neuronal death. Because similar energetic perturbations occur in ischemic mitochondria, this study provides a basis for generating hypotheses for investigating analogous TDP-43 pathways in the context of stroke.
Author Manuscript
Neuronal mitochondria play important roles in maintaining neuronal function and survival in a cell-autonomous fashion (e.g. via intracellular mechanisms). However, mitochondria in other types of cells may also contribute to impact neuronal function under diseased conditions. Chikka et al (The Mitochondria-Regulated Immune Pathway Activated in the C. elegans Intestine Is Neuroprotective. Cell Reports. 2016;16:1–6) showed that mitochondrial dysfunction in intestinal cells would activate immune pathways, which acts as neuroprotective. The authors exposed c. elegans to the mitotoxin rotenone stimulation as a
Corresponding author: Ken Arai, Ph.D., Neuroprotection Research Laboratory, MGH East 149-2401, Charlestown, MA 02129, USA. Tel: 617.724.9503, [email protected].
Arai
Page 2
Author Manuscript Author Manuscript
model system of neurodegenerative disorders. Upon rotenon exposure, p38MAPK/ATF-7 signaling in intestinal cells was activated due to mitochondrial complex I dysfunction. Overexpression of p38MAPK only in the gut increased ATF-7 target gene expression upon rotenone exposure compared to controls, which resulted in suppressing rotenone-induced dopaminergic neuron degeneration. Also, overexpression of inactive p38MAPK in the gut exhibited dopaminergic neuronal damage by rotenone exposure. For the underlying mechanisms, the authors demonstrated that P38MAPK/ATF-7 activation decreased oxidative damage through the removal of dysfunctional mitochondria by mirochondrial autophagy (e.g. mitophagy). Taken together, these data suggest that mitochondria in intestinal cells may protect neurons in a non-cell-autonomous fashion under diseased conditions. An emerging literature now points to the importance of crosstalk between the gut and post-stroke inflammation that may be mediated by the microbiome. This study suggests that mitochondrial responses may also be involved in these critical pathways of centralperipheral crosstalk.
Author Manuscript
Hayakawa et al (Transfer of mitochondria from astrocytes to neurons after stroke. Nature;535:551–555) proposes that non-cell autonomous signaling within the neurovascular unit may also involve the exchange of mitochondria. In this study, astrocytes may actively release functional mitochondria via calcium-dependent mechanisms, and neighboring neurons that incorporated those astrocyte-derived mitochondria became more resistant to ischemic stress. The authors first conducted cell culture experiments to confirm the existence of functional mitochondria in astrocyte-conditioned culture media. They also showed that astrocyte-derived mitochondria-contained culture media indeed protected neurons against oxygen-glucose deprivation. In addition, cultured neurons absorbed astrocyte-derived mitochondia under the stressed conditions, and this mitochondria transfer was mediated via CD38/cyclic-ADP signaling in astrocytes because siRNA suppression of CD38 in astrocytes reduced the transfer in the astrocyte-neuron co-culture system. Correspondingly, in an in vivo mouse model of transient focal ischemia, neurons in periinfarct areas appeared to contain astrocyte-derived mitochondria. Furthermore, CD38suppression by siRNA decreased the mitochondria transfer from astrocytes to neurons and worsened the neurological deficits without affecting the number of CD38-expressing immune cells in brain. These data implied that under diseased conditions, mitochondria may travel from astrocytes to neurons as part of an endogenous program to protect and support neurons at risk.
Author Manuscript
These three new studies all demonstrate the central role of novel mitochondrial mechanisms that may help regulate neuronal function under diseased conditions. Further investigations are warranted to determine whether and how these mechanisms may be leveraged or targeted for improving outcomes in stroke patient.
Stroke. Author manuscript; available in PMC 2017 November 01.
