scholarly journals Mitochondrial retrograde signaling regulates neuronal function

2015 ◽  
Vol 112 (44) ◽  
pp. E6000-E6009 ◽  
Author(s):  
Umut Cagin ◽  
Olivia F. Duncan ◽  
Ariana P. Gatt ◽  
Marc S. Dionne ◽  
Sean T. Sweeney ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Hypoxia Inducible Factor ◽  
Leigh Syndrome ◽  
Retrograde Signaling ◽  
Neuronal Function ◽  
Mitochondrial Retrograde Signaling ◽  
Factor Alpha ◽  
Familial Parkinson’S Disease ◽  
Mitochondrial Defect

Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. Neuronal mitochondrial dysfunction causes reduced viability, defects in neuronal function, decreased redox potential, and reduced numbers of presynaptic mitochondria and active zones. We find that neuronal mitochondrial dysfunction stimulates a retrograde signaling response that controls the expression of several hundred nuclear genes. We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson’s disease. Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment.

scholarly journals Ndufs4 ablation decreases synaptophysin expression in hippocampus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Subrata Kumar Shil ◽  
Yoshiteru Kagawa ◽  
Banlanjo Abdulaziz Umaru ◽  
Fumika Nanto-Hara ◽  
Hirofumi Miyazaki ◽  
...  
Keyword(s):  
Nadh Dehydrogenase ◽  
Leigh Syndrome ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Activity ◽  
Mitochondrial Complex ◽  
Neuronal Function ◽  
Mouse Hippocampus ◽  
Extracellular Regulated Kinase ◽  
Presynaptic Protein

AbstractAltered function of mitochondrial respiratory chain in brain cells is related to many neurodegenerative diseases. NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and its mutation in human is associated with Leigh syndrome. However, the molecular biological role of Ndufs4 in neuronal function is poorly understood. In this study, upon Ndufs4 expression confirmation in NeuN-positive neurons, and GFAP-positive astrocytes in WT mouse hippocampus, we found significant decrease of mitochondrial respiration in Ndufs4-KO mouse hippocampus. Although there was no change in the number of NeuN positive neurons in Ndufs4-KO hippocampus, the expression of synaptophysin, a presynaptic protein, was significantly decreased. To investigate the detailed mechanism, we silenced Ndufs4 in Neuro-2a cells and we observed shorter neurite lengths with decreased expression of synaptophysin. Furthermore, western blot analysis for phosphorylated extracellular regulated kinase (pERK) revealed that Ndufs4 silencing decreases the activity of ERK signalling. These results suggest that Ndufs4-modulated mitochondrial activity may be involved in neuroplasticity via regulating synaptophysin expression.

scholarly journals Mitochondrial dysfunction, UPRmt signaling, and targeted therapy in metastasis tumor

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rajendiran Keerthiga ◽  
De-Sheng Pei ◽  
Ailing Fu
Keyword(s):  
Targeted Therapy ◽  
Mitochondrial Dysfunction ◽  
Tumor Cells ◽  
Hypoxia Inducible Factor ◽  
Retrograde Signaling ◽  
Protein Accumulation ◽  
Mtdna Mutation ◽  
Unfolded Protein ◽  
Denatured Protein ◽  
Activating Transcription Factor

AbstractIn modern research, mitochondria are considered a more crucial energy plant in cells. Mitochondrial dysfunction, including mitochondrial DNA (mtDNA) mutation and denatured protein accumulation, is a common feature of tumors. The dysfunctional mitochondria reprogram molecular metabolism and allow tumor cells to proliferate in the hostile microenvironment. One of the crucial signaling pathways of the mitochondrial dysfunction activation in the tumor cells is the retrograde signaling of mitochondria-nucleus interaction, mitochondrial unfolded protein response (UPRmt), which is initiated by accumulation of denatured protein and excess ROS production. In the process of UPRmt, various components are activitated to enhance the mitochondria-nucleus retrograde signaling to promote carcinoma progression, including hypoxia-inducible factor (HIF), activating transcription factor ATF-4, ATF-5, CHOP, AKT, AMPK. The retrograde signaling molecules of overexpression ATF-5, SIRT3, CREB, SOD1, SOD2, early growth response protein 1 (EGR1), ATF2, CCAAT/enhancer-binding protein-d, and CHOP also involved in the process. Targeted blockage of the UPRmt pathway could obviously inhibit tumor proliferation and metastasis. This review indicates the UPRmt pathways and its crucial role in targeted therapy of metastasis tumors.

scholarly journals Ras-ERK-ETS inhibition alleviates neuronal mitochondrial dysfunction by reprogramming mitochondrial retrograde signaling

PLoS Genetics ◽  
2018 ◽  
Vol 14 (7) ◽  
pp. e1007567 ◽  
Author(s):  
Olivia F. Duncan ◽  
Lucy Granat ◽  
Ramya Ranganathan ◽  
Vandana K. Singh ◽  
David Mazaud ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Retrograde Signaling ◽  
Mitochondrial Retrograde Signaling

scholarly journals Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective

2021 ◽  
Vol 12 ◽  
Author(s):  
Patrycja Mulica ◽  
Anne Grünewald ◽  
Sandro L. Pereira
Keyword(s):  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Therapeutic Potential ◽  
Special Focus ◽  
Neuronal Function ◽  
Supportive Role ◽  
The Brain ◽  
And Oxidative Stress ◽  
Brain Energetics

Converging evidence made clear that declining brain energetics contribute to aging and are implicated in the initiation and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Indeed, both pathologies involve instances of hypometabolism of glucose and oxygen in the brain causing mitochondrial dysfunction, energetic failure and oxidative stress. Importantly, recent evidence suggests that astrocytes, which play a key role in supporting neuronal function and metabolism, might contribute to the development of neurodegenerative diseases. Therefore, exploring how the neuro-supportive role of astrocytes may be impaired in the context of these disorders has great therapeutic potential. In the following, we will discuss some of the so far identified features underlining the astrocyte-neuron metabolic crosstalk. Thereby, special focus will be given to the role of mitochondria. Furthermore, we will report on recent advancements concerning iPSC-derived models used to unravel the metabolic contribution of astrocytes to neuronal demise. Finally, we discuss how mitochondrial dysfunction in astrocytes could contribute to inflammatory signaling in neurodegenerative diseases.

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