Mechanisms of Mitochondria-Neurofilament Interactions

Wagner, Oliver I.; Lifshitz, Jonathan; Janmey, Paul A.; Lindén, Monica; McIntosh, Tracy K.; Leterrier, J.F.

doi:10.1523/jneurosci.23-27-09046.2003

Cited by 165 publications

(168 citation statements)

References 79 publications

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“…Further, during myelinogenesis, oligodendrocytes elaborate extensive membrane sheets at a dramatic rate (1), placing an enormous energetic demand on the cell. Mitochondria are often anchored by the cytoskeleton at regions of high ATP consumption (47). It is plausible that at least part of this demand is supplied by local ''myelin mitochondria.''…”

Section: Discussionmentioning

confidence: 99%

Proteomic mapping provides powerful insights into functional myelin biology

Taylor

Marta

Claycomb

et al. 2004

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

109

107

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Myelin is a dynamic, functionally active membrane necessary for rapid action potential conduction, axon survival, and cytoarchitecture. The number of debilitating neurological disorders that occur when myelin is disrupted emphasizes its importance. Using highresolution 2D gel electrophoresis, mass spectrometry, and immunoblotting, we have developed an extensive proteomic map of proteins present in myelin, identifying 98 proteins corresponding to at least 130 of the Ϸ200 spots on the map. This proteomic map has been applied to analyses of the localization and function of selected proteins, providing a powerful tool to investigate the diverse functions of myelin.M yelin is a dynamic, functionally active membrane (1), the loss or damage of which results in serious neurological disorders including leukodystrophies, central and peripheral neuropathies, and inflammatory demyelinating diseases such as multiple sclerosis (2-4). Rapid and efficient action potential conduction in the nervous system depends on myelin, which traditionally has been viewed as a passive contributor to conduction by increasing internodal membrane resistance and decreasing membrane capacitance (5). However, recent work has revealed additional active roles for myelin in nervous system development and function. For example, myelin regulates axon diameter and the formation of axon microtubular networks, and it is a key player in ion channel clustering at nodes of Ranvier (6-11). In return, the axon regulates myelin gene expression (12) and oligodendrocyte survival (13). The functional coupling of myelin and axons is further illustrated by the transfer of phospholipids (14) and N-acetylaspartate (15) from the axon to the myelin sheath.A major impediment to understanding the active biological functions of myelin is the relative lack of myelin proteins that have been described and characterized. Thus, we have undertaken an extensive proteomic analysis of central nervous system myelin, developed a 2D PAGE map of myelin proteins, identified 98 of these proteins, and illustrated the power and utility of this approach through specific applications of comparative proteomics. For example, a comparison of CNS and peripheral nervous system (PNS) myelin proteins has revealed a previously undescribed component of Schwann cell microvilli, a proteomic matching of myelin from normal and genetically modified mice lacking key myelin lipids has demonstrated a dramatic reduction of two newly recognized myelin protein kinases, and an application of the map to a neuroimmunological analysis of demyelinating disease has identified a signaling mechanism (16).

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Section: Discussionmentioning

confidence: 99%

Proteomic mapping provides powerful insights into functional myelin biology

Taylor

Marta

Claycomb

et al. 2004

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

109

107

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“…We suggest that mitochondria with fresh, cell body-derived components generate a local signal that represses cytoplasmic dynein, activates kinesin-1, and thus dictates anterograde transport toward the terminal. In the axon, areas requiring ATP generate local signals that convert anterograde mitochondria to stationary by activating static cross-links with the cytoskeleton (Forman et al, 1987;Chada and Hollenbeck, 2003;Wagner et al, 2003;Miller and Sheetz, 2004;Hollenbeck and Saxton, 2005). Over time, damage to mitochondrial components from reactive oxygen species causes a decline in energy-producing capacity (Hagen et al, 1997) that triggers release from cytoskeletal anchoring, activation of dynein, and repression of kinesin-1.…”

Section: Directional Programmingmentioning

confidence: 99%

Kinesin-1 and Dynein Are the Primary Motors for Fast Transport of Mitochondria inDrosophilaMotor Axons

Pilling

Horiuchi

Lively

et al. 2006

MBoC

618

621

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To address questions about mechanisms of filament-based organelle transport, a system was developed to image and track mitochondria in an intact Drosophila nervous system. Mutant analyses suggest that the primary motors for mitochondrial movement in larval motor axons are kinesin-1 (anterograde) and cytoplasmic dynein (retrograde), and interestingly that kinesin-1 is critical for retrograde transport by dynein. During transport, there was little evidence that force production by the two opposing motors was competitive, suggesting a mechanism for alternate coordination. Tests of the possible coordination factor P150 Glued suggested that it indeed influenced both motors on axonal mitochondria, but there was no evidence that its function was critical for the motor coordination mechanism. Observation of organelle-filled axonal swellings ("organelle jams" or "clogs") caused by kinesin and dynein mutations showed that mitochondria could move vigorously within and pass through them, indicating that they were not the simple steric transport blockades suggested previously. We speculate that axonal swellings may instead reflect sites of autophagocytosis of senescent mitochondria that are stranded in axons by retrograde transport failure; a protective process aimed at suppressing cell death signals and neurodegeneration. INTRODUCTIONOrganelle transport is central to the organization, developmental fate, and functions of asymmetric cells. A bipolar neuron is an extreme case, with the somato-dendritic region and the axon containing different sets of proteins and organelles. In general, much of the machinery for synthesizing and recycling neuronal components is clustered near the nucleus. Because an axon, often with an axial ratio of many thousands, usually contains Ͼ99% of the neuronal cytoplasm, active transport of new components away from the cell body and of spent components and trophic materials back toward the cell body is critical. Disruptions of axonal transport are thought to contribute to the pathologies of Alzheimer's, amyotrophic lateral sclerosis, and other neurodegenerative diseases (reviewed by Mandelkow and Mandelkow, 2002;Hirokawa and Takemura, 2005).Long-distance organelle transport in axons is driven by motor proteins that move along parallel microtubules whose plus ends are mostly oriented toward the axon terminal (reviewed by Hollenbeck and Saxton, 2005). There are multiple types of microtubule motors in postmitotic vertebrate neurons, including kinesins that can move toward either plus-or minus-ends and at least one cytoplasmic dynein that moves toward minus-ends (Martin et al., 1999b;Hirokawa and Takemura, 2005;Hollenbeck and Saxton, 2005). Which motors bind and move which axonal components? When multiple types of motors bind a single cargo, do they collaborate or compete, how are they regulated, and how do their combined activities generate an optimal distribution of that type of cargo?Axonal mitochondria are critical for the physiology of neurons and are particularly well suited for studying active tr...

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“…This could be an ion such as Ca 2+ (Budd and Nicholls, 1996;Kanai et al, 2001;Kanje et al, 1981;Kendal et al, 1983;Ochs and Jersild, 1984;Ochs et al, 1977), a metabolite such as ATP (de Graaf et al, 2000), creatine (van Deursen et al, 1993), ADP or NADH (BereiterHahn and Voth, 1983;Bereiter-Hahn and Voth, 1994), a second messenger such as a small G-protein (Alto et al, 2002;Fransson et al, 2003), or another signal-transduction pathway (Chada and Hollenbeck, 2003). It follows that the concentration of the molecule alters a sensor that regulates activity of a motor (as discussed below) or linker between the mitochondria and cytoskeleton (Boldogh et al, 1998;Trinczek et al, 1999;Wagner et al, 2003). The sensor could be either positioned in the cytoplasm or associated with the mitochondria.…”

Section: Local Drug Applicationmentioning

confidence: 99%

Axonal mitochondrial transport and potential are correlated

Miller

Sheetz

2004

Journal of Cell Science

460

387

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Disruption of axonal transport leads to a disorganized distribution of mitochondria and other organelles and is thought to be responsible for some types of neuronal disease. The reason for bidirectional transport of mitochondria is unknown. We have developed and applied a set of statistical methods and found that axonal mitochondria are uniformly distributed. Analysis of fast axonal transport showed that the uniform distribution arose from the clustering of the stopping events of fast axonal transport in the middle of the gaps between stationary mitochondria. To test whether transport was correlated with ATP production, we added metabolic inhibitors locally by micropipette. Whereas applying CCCP (a mitochondrial uncoupler) blocked mitochondrial transport, as has been previously reported, treatment with antimycin (an inhibitor of electron transport at complex III) caused increases in retrograde mitochondrial transport. Application of 2-deoxyglucose did not decrease transport compared with the mannitol control. To determine whether mitochondrial transport was correlated with mitochondrial potential, we stained the neurons with the mitochondrial potential-sensing dye JC-1. We found that ∼90% of mitochondria with high potential were transported towards the growth cone and ∼80% of mitochondria with low potential were transported towards the cell body. These experiments show for the first time that a uniform mitochondrial distribution is generated by local regulation of the stopping events of fast mitochondrial transport, and that the direction of mitochondrial transport is correlated with mitochondrial potential. These results have implications for axonal clogging, autophagy, apoptosis and Alzheimer's disease.

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Mechanisms of Mitochondria-Neurofilament Interactions

Cited by 165 publications

References 79 publications

Proteomic mapping provides powerful insights into functional myelin biology

Proteomic mapping provides powerful insights into functional myelin biology

Kinesin-1 and Dynein Are the Primary Motors for Fast Transport of Mitochondria inDrosophilaMotor Axons

Axonal mitochondrial transport and potential are correlated

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