Complexity of mitochondrial dynamics in neurons and its control by ADP produced during synaptic activity

Mironov, S.L.

doi:10.1016/j.biocel.2009.04.009

Cited by 34 publications

(34 citation statements)

References 75 publications

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“…6B). Mitochondria play important roles in cellular energy metabolism and ATP generation (28). High metabolic activity of mitochondria results in the generation of reactive oxygen species (29).…”

Section: Resultsmentioning

confidence: 99%

Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons

et al. 2011

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Insulin resistance (IR) is the major feature of metabolic syndrome, including type 2 diabetes. IR studies are mainly focused on peripheral tissues, such as muscle and liver. There is, however, little knowledge about IR in neurons. In this study, we examined whether neurons develop IR in response to hyperinsulinemia. We first examined insulin signaling using adult dorsal root ganglion neurons as a model system. Acute insulin treatment resulted in time- and concentration-dependent activation of the signaling cascade, including phosphorylation of the insulin receptor, Akt, p70S6K, and glycogen synthase kinase-3β. To mimic hyperinsulinemia, cells were pretreated with 20 nM insulin for 24 h and then stimulated with 20 nM insulin for 15 min. Chronic insulin treatment resulted in increased basal Akt phosphorylation. More importantly, acute insulin stimulation after chronic insulin treatment resulted in blunted phosphorylation of Akt, p70S6K, and glycogen synthase kinase-3β. Interestingly, when the cells were treated with phosphatidylinositol 3-kinase pathway inhibitor, but not MAPK pathway inhibitor, chronic insulin treatment did not block acute insulin treatment-induced Akt phosphorylation. Insulin-induced Akt phosphorylation was lower in dorsal root ganglion neurons from BKS-db/db compared with control BKS-db+ mice. This effect was age dependent. Our results suggest that hyperinsulinemia cause IR by disrupting the Akt-mediated pathway. We also demonstrate that hyperinsulinemia increases the mitochondrial fission protein dynamin-related protein 1. Our results suggest a new theory for the etiology of diabetic neuropathy, i.e. that, similar to insulin dependent tissues, neurons develop IR and, in turn, cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury and the development of neuropathy.

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Section: Resultsmentioning

confidence: 99%

Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons

et al. 2011

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“…The preferential presence of UCP4 or ATP synthase in mitochondria can be rationalized by different energy demands in various neuronal areas. Energy demand is especially high in synapses, which require mitochondria containing higher levels of ATP synthase (26). The prevalence of highly energized mitochondria was observed in the periphery of several cells, including cortical neurons (23).…”

Section: Resultsmentioning

confidence: 99%

Superresolution microscopy reveals spatial separation of UCP4 and F ₀ F ₁ -ATP synthase in neuronal mitochondria

Klotzsch

Smorodchenko²,

Löfler

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Because different proteins compete for the proton gradient across the inner mitochondrial membrane, an efficient mechanism is required for allocation of associated chemical potential to the distinct demands, such as ATP production, thermogenesis, regulation of reactive oxygen species (ROS), etc. Here, we used the superresolution technique dSTORM (direct stochastic optical reconstruction microscopy) to visualize several mitochondrial proteins in primary mouse neurons and test the hypothesis that uncoupling protein 4 (UCP4) and F 0 F 1 -ATP synthase are spatially separated to eliminate competition for the proton motive force. We found that UCP4, F 0 F 1 -ATP synthase, and the mitochondrial marker voltage-dependent anion channel (VDAC) have various expression levels in different mitochondria, supporting the hypothesis of mitochondrial heterogeneity. Our experimental results further revealed that UCP4 is preferentially localized in close vicinity to VDAC, presumably at the inner boundary membrane, whereas F 0 F 1 -ATP synthase is more centrally located at the cristae membrane. The data suggest that UCP4 cannot compete for protons because of its spatial separation from both the proton pumps and the ATP synthase. Thus, mitochondrial morphology precludes UCP4 from acting as an uncoupler of oxidative phosphorylation but is consistent with the view that UCP4 may dissipate the excessive proton gradient, which is usually associated with ROS production. mitochondrial membrane proteins | proton diffusion | direct stochastic optical reconstruction microscopy | uncoupling | reactive oxygen species M itochondria are involved in a wide range of cell functions, including fatty acid oxidation, calcium homeostasis, apoptosis, reactive oxygen species (ROS) signaling, and above all, production of ATP (1, 2). In neurons, these organelles are transported along neuronal processes to provide energy for areas of high energy demand, such as synapses (3). To support their functions, mitochondria exhibit a complex morphology consisting of separate and functionally distinct outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM). The latter is structurally organized into two domains: an inner boundary membrane (IBM) and a cristae membrane (CM) (4). The current hypotheses imply that the morphology/topology of the IMM is tightly related to biochemical function, the energy state, and the pathophysiological state of mitochondria (5). Whereas the OMM contains porins [e.g., voltage-dependent anion channel (VDAC)], which mediate its permeability to molecules up to 10 kDa, the IMM topology is highly complex. It is comprised of different transport proteins, the ATP synthase (complex V), and complexes I, III, and IV of the electron transport chain, which are responsible for generating the proton motive force (pmf); pmf represents the driving force for not only ATP synthesis, but also other protein-mediated transport activities (for example, phosphate, pyruvate, and glutamate transport). Uncoupling protein 1 (UCP1; thermogenin), a memb...

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“…It is unknown whether BCK associates to these. Further, the process is energetically supported by mitochondria at the presynaptic membrane (Gazzaniga et al 2004;Squire and Zigmond 2002;Mironov 2009), showing that although brain is mainly glycolytic, mitochondria play important roles. Interestingly, we have detected BCK in mitochondrial fractions from rat brain (Tokarska- ).…”

Section: Searching For Novel Bck Microcompartmentsmentioning

confidence: 96%

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

et al. 2016

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There is an increasing body of evidence for local circuits of ATP generation and consumption that are largely independent of global cellular ATP levels. These are mostly based on the formation of multiprotein(-lipid) complexes and diffusion limitations existing in cells at different levels of organization, e.g., due to the viscosity of the cytosolic medium, macromolecular crowding, multiple and bulky intracellular structures, or controlled permeability across membranes. Enzymes generating ATP or GTP are found associated with ATPases and GTPases enabling the direct fueling of these energy-dependent processes, and thereby implying that it is the local and not the global concentration of high-energy metabolites that is functionally relevant. A paradigm for such microcompartmentation is creatine kinase (CK). Cytosolic and mitochondrial isoforms of CK constitute a well established energy buffering and shuttling system whose functions are very much based on local association of CK isoforms with ATP-providing and ATP-consuming processes. Here we review current knowledge on the subcellular localization and direct protein and lipid interactions of CK isoforms, in particular about cytosolic brain-type CK (BCK) much less is known compared to muscle-type CK (MCK). We further present novel data on BCK, based on three different experimental approaches: (1) co-purification experiments, suggesting association of BCK with membrane structures such as synaptic vesicles and mitochondria, involving hydrophobic and electrostatic interactions, respectively; (2) yeast-two-hybrid analysis using cytosolic split-protein assays and the identifying membrane proteins VAMP2, VAMP3 and JWA as putative BCK interaction partners; and (3) phosphorylation experiments, showing that the cellular energy sensor AMP-activated protein kinase (AMPK) is able to phosphorylate BCK at serine 6 to trigger BCK localization at the ER, in close vicinity of the highly energy-demanding Ca(2+) ATPase pump. Thus, membrane localization of BCK seems to be an important and regulated feature for the fueling of membrane-located, ATP-dependent processes, stressing again the importance of local rather than global ATP concentrations.

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Complexity of mitochondrial dynamics in neurons and its control by ADP produced during synaptic activity

Cited by 34 publications

References 75 publications

Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons

Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons

Superresolution microscopy reveals spatial separation of UCP4 and F ₀ F ₁ -ATP synthase in neuronal mitochondria

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

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Complexity of mitochondrial dynamics in neurons and its control by ADP produced during synaptic activity

Cited by 34 publications

References 75 publications

Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons

Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons

Superresolution microscopy reveals spatial separation of UCP4 and F 0 F 1 -ATP synthase in neuronal mitochondria

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

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Superresolution microscopy reveals spatial separation of UCP4 and F ₀ F ₁ -ATP synthase in neuronal mitochondria