Long-Term Potentiation Requires a Rapid Burst of Dendritic Mitochondrial Fission during Induction

Divakaruni, Sai Sachin; Dyke, Adam M. Van; Chandra, Ramesh; LeGates, Tara A.; Contreras, Minerva; Dharmasri, Poorna A.; Higgs, Henry N.; Lobo, Mary Kay; Thompson, Scott M.; Blanpied, Thomas A.

doi:10.1016/j.neuron.2018.09.025

Cited by 109 publications

(123 citation statements)

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“…Increased smaller size mitochondria is associated with enhanced fission, which mediates structural and synaptic plasticity (Cassidy-Stone et al, 2008;Chen et al, 2007;Divakaruni et al, 2018;Ishihara et al, 2009;Li et al, 2004). However, fission molecules, including Drp1 which is associated with enhanced structural and synaptic plasticity Divakaruni et al, 2018;Li et al, 2004), were similar between NAc MSN subtypes. Thus, the smaller mitochondria observed in D2 MSNs may represent reduced fusion as addressed above.…”

Section: Discussionmentioning

confidence: 94%

“…D2-MSNs display increased sEPSC frequency in NAc core and shell (Ma et al, 2013); however, another study examining NAc MSN subtypes in prepubertal mice demonstrated reduced mEPSC frequency in D2-MSNs in NAc core (Willett et al, 2018). However, fission molecules, including Drp1 which is associated with enhanced structural and synaptic plasticity Divakaruni et al, 2018;Li et al, 2004), However, fission molecules, including Drp1 which is associated with enhanced structural and synaptic plasticity Divakaruni et al, 2018;Li et al, 2004),…”

Section: Discussionmentioning

confidence: 97%

“…Indeed, in D1 MSNs after cocaine self-administration, the mitochondrial index in proximal dendrites is reduced . Individual mitochondria impact neuronal excitability via alterations in dendritic spine formation and maintenance (Divakaruni et al, 2018;Li et al, 2004), which may be how differentially sized mitochondria contribute to the differences in baseline electrophysiological properties of NAc MSN subtypes.…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondria play key roles in neurons, and are involved in cell physiology, buffering of calcium levels, ROS maintenance, and regulation of neuronal plasticity (Li, Okamoto, Hayashi, & Sheng, 2004;Rueda et al, 2014;Vos, Lauwers, & Verstreken, 2010). These processes are critical for maintenance of mitochondrial function, cellular quality control, and can play a role in neuronal plasticity and structure (Cassidy-Stone et al, 2008;Chen, McCaffery, & Chan, 2007;Divakaruni et al, 2018;Li et al, 2004). Outer membrane protein Dynamin-1-like protein (Drp1) and mitochondrial fission 1 molecules (Fis1) are involved in mitochondrial fission, while inner mitochondrial membrane protein, mitochondrial dynamin like GTPase (Opa1), outer membrane protein, Mitofusin 1 (Mfn1), and Mitofusin 2 (Mfn2) molecules are involved in mitochondrial fusion (Detmer & Chan, 2007;Friedman & Nunnari, 2014;Westermann, 2010).…”

mentioning

confidence: 99%

“…Outer membrane protein Dynamin-1-like protein (Drp1) and mitochondrial fission 1 molecules (Fis1) are involved in mitochondrial fission, while inner mitochondrial membrane protein, mitochondrial dynamin like GTPase (Opa1), outer membrane protein, Mitofusin 1 (Mfn1), and Mitofusin 2 (Mfn2) molecules are involved in mitochondrial fusion (Detmer & Chan, 2007;Friedman & Nunnari, 2014;Westermann, 2010). These processes are critical for maintenance of mitochondrial function, cellular quality control, and can play a role in neuronal plasticity and structure (Cassidy-Stone et al, 2008;Chen, McCaffery, & Chan, 2007;Divakaruni et al, 2018;Li et al, 2004). While most studies have not examined MSN subtype mitochondrial differences, recent studies are beginning to perform this analysis.…”

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confidence: 99%

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Differential mitochondrial morphology in ventral striatal projection neuron subtypes

Chandra

Calarco

Lobo

2019

J of Neuroscience Research

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The two striatal projection neuron subtypes (medium spiny neurons‐ MSNs), those enriched in dopamine receptor 1 versus 2 (D1‐MSNs and D2‐MSNs), display dichotomous properties at the level of the transcriptome, projections, morphology, and electrophysiology. Recent work illustrates dichotomous mitochondrial length in NAc MSN subtype dendrites after cocaine self‐administration, with a shift toward smaller mitochondria, due to enhanced fission, occurring in D1‐MSN dendrites and a shift toward larger mitochondria in D2‐MSN dendrites. However, to date there has been no comparison of mitochondrial morphological properties between MSN subtypes. In this study, we examine mitochondrial morphology in NAc D1‐MSNs versus D2‐MSNs. We observe an increase in the frequency of smaller length mitochondria in D2‐MSN dendrites relative to D1‐MSN dendrites, while D1‐MSN dendrites display an increase in larger length mitochondria. The differences in mitochondrial length occur in both NAc core and shell, although to a greater extent in NAc core. Finally, we demonstrate that the mitochondrial fusion molecule, Opa1, is differentially expressed in NAc MSN subtypes, with D1‐MSNs displaying higher expression of Opa1 ribosome‐associated mRNA. The difference in Opa1 levels may account for the bias toward enhanced smaller mitochondria in D2‐MSNs and enhanced larger mitochondria in D1‐MSNs. Collectively, our study demonstrates differential mitochondrial size and a potential molecular mediator of these mitochondrial differences in NAc MSN subtypes.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Differential mitochondrial morphology in ventral striatal projection neuron subtypes

Chandra

Calarco

Lobo

2019

J of Neuroscience Research

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Mitochondria in Neuronal Health: From Energy Metabolism to Parkinson's Disease

et al. 2021

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dendrites, as well as the synthesis of proteins upon stimulation, add to the neuronal energy usage. In this review, we discuss how this enormous amount of ATP is supplied by the different routes of ATP generation and is altered in disease states.Energy metabolism is mediated by the interplay of cytosolic glycolysis with mitochondrial oxidative phosphorylation (OXPHOS). Glucose is the main energy source for the brain and is first imported into the cytoplasm of neurons or astrocytes and converted to pyruvate via glycolysis. Pyruvate is then transported across the mitochondrial membranes and decarboxylated to form acetyl-CoenzymeA (acetyl-CoA). Acetyl-CoA is also the final product of fatty acid β-oxidation, which can occur in mitochondria or peroxisomes alike. Another source of acetyl-CoA is ketone bodies derived from fatty acid oxidation in the liver and secreted into the bloodstream for uptake by extrahepatic tissues. Acetyl-CoA from various sources can then enter the tricarboxylic acid (TCA) cycle to produce the reducing equivalents NADH and FADH, which will finally be fed into the respiratory chain to produce ATP.Although mitochondria are essential for OXPHOS, they are more than just the "powerhouse of the cell," as they also regulate several catabolic processes, such as amino acid or steroid synthesis, influence Ca 2+ and redox equivalent concentrations in the cytosol, and are crucial hubs in the execution of cell death (Figure 1). Thus, it is impossible to review mitochondrial energy metabolism in health and disease without discussing other mitochondrial functions. Therefore, we will briefly describe our current knowledge of mitochondrial function in other catabolic and homeostatic processes. Further, we discuss the cellular responses to mitochondrial dysfunction and how these pathways enhance or deteriorate the pathogenesis of Parkinson's (PD), a neurodegenerative disease that is deeply linked to mitochondrial dysfunction. ATP Sources in NeuronsUnlike most metabolically demanding tissues such as muscle, neurons do not have significant energy stores in the form of glycogen, lipids, or creatine phosphate. [4] As a result, neuronal energy metabolism is tightly regulated, and even acute interruptions in fuel supply rapidly suppress cognitive function. Below, we discuss some of the important sources of ATP in neurons and their contribution to energetic homeostasis and neuronal survival. Mitochondria are the main suppliers of neuronal adenosine triphosphate and play a critical role in brain energy metabolism. Mitochondria also serve as Ca 2+ sinks and anabolic factories and are therefore essential for neuronal function and survival. Dysregulation of neuronal bioenergetics is increasingly implicated in neurodegenerative disorders, particularly Parkinson's disease. This review describes the role of mitochondria in energy metabolism under resting conditions and during synaptic transmission, and presents evidence for the contribution of neuronal mitochondrial dysfunction to Parkinson's disease.

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Layer‐specific mitochondrial diversity across hippocampal CA2 dendrites

et al. 2023

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CA2 is an understudied subregion of the hippocampus that is critical for social memory. Previous studies identified multiple components of the mitochondrial calcium uniporter (MCU) complex as selectively enriched in CA2. The MCU complex regulates calcium entry into mitochondria, which in turn regulates mitochondrial transport and localization to active synapses. We found that MCU is strikingly enriched in CA2 distal apical dendrites, precisely where CA2 neurons receive entorhinal cortical input carrying social information. Furthermore, MCU-enriched mitochondria in CA2 distal dendrites are larger compared to mitochondria in CA2 proximal apical dendrites and neighboring CA1 apical dendrites, which was confirmed in CA2 with genetically labeled mitochondria and electron microscopy. MCU overexpression in neighboring CA1 led to a preferential localization of MCU in the proximal dendrites of CA1 compared to the distal dendrites, an effect not seen in CA2. Our findings demonstrate that mitochondria are molecularly and structurally diverse across hippocampal cell types and circuits, and suggest that MCU can be differentially localized within dendrites, possibly to meet local energy demands.

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Long-Term Potentiation Requires a Rapid Burst of Dendritic Mitochondrial Fission during Induction

Cited by 109 publications

References 88 publications

Differential mitochondrial morphology in ventral striatal projection neuron subtypes

Differential mitochondrial morphology in ventral striatal projection neuron subtypes

Mitochondria in Neuronal Health: From Energy Metabolism to Parkinson's Disease

Layer‐specific mitochondrial diversity across hippocampal CA2 dendrites

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