Stroke Literature Synopses: Basic Science
The mitochondrion is the major organelle responsible for energy generation to maintain cellular homeostasis. Mitochondrial dysfunction is observed in many central nervous system diseases including stroke. Three recent studies summarized below provide novel insights into mitochondrial mechanisms that may impact neuronal function.
Wang et al (The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat Med. 2016;32:869–878. doi: 10.1038/nm.4130.) revealed that mitochondrial localization of TDP-43 (TAR DNA-binding protein 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 central nervous system diseases, such as amyotrophic lateral sclerosis or frontotemporal dementia. To examine the underlying molecular mechanisms, the authors first investigated the colocalization of TDP-43 with neuronal organelles in central nervous system samples from amyotrophic lateral sclerosis and frontotemporal dementia patients. Compared with the control cases, amyotrophic lateral sclerosis motor neurons and frontotemporal dementia cortical neurons exhibited high levels of cytoplasmic TDP-43 accumulation, and the cytoplasmic TDP-43 was colocalized 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-associated 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.
Neuronal mitochondria play important roles in maintaining neuronal function and survival in a cell-autonomous fashion (eg, 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 Rep. 2016;16:2399–2414. doi: 10.1016/j.celrep.2016.07.077.) showed that mitochondrial dysfunction in intestinal cells would activate immune pathways, which acts as neuroprotective. The authors exposed Caenorhabditiselegans to the mitotoxin rotenone stimulation as a model system of neurodegenerative disorders. On rotenon exposure, p38MAPK/ATF-7 signaling in intestinal cells was activated because of mitochondrial complex I dysfunction. Overexpression of p38MAPK only in the gut increased ATF-7 target gene expression on rotenone exposure compared with 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 mitochondrial autophagy (eg, 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 poststroke inflammation that may be mediated by the microbiome. This study suggests that mitochondrial responses may also be involved in these critical pathways of central–peripheral crosstalk.
Hayakawa et al (Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016;535:551–555. doi: 10.1038/nature18928.) 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 mitochondria 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 coculture system. Correspondingly, in an in vivo mouse model of transient focal ischemia, neurons in peri-infarct areas seemed to contain astrocyte-derived mitochondria. Furthermore, CD38 suppression by siRNA decreased the mitochondrial 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.
These 3 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.
- © 2016 American Heart Association, Inc.