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Mitochondrial quality control and neurological disease: an emerging connection.

de Castro IP, Martins LM, Tufi R - Expert Rev Mol Med (2010)

Bottom Line: Mitochondria have a crucial role in the supply of energy to the brain.Consequently, their deterioration can have important detrimental consequences on the function and plasticity of neurons, and is thought to have a pivotal role in ageing and in the pathogenesis of several neurological disorders.Owing to their inherent physiological functions, mitochondria are subjected to particularly high levels of stress and have evolved specific molecular quality-control mechanisms to maintain the mitochondrial components.

View Article: PubMed Central - PubMed

Affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.

ABSTRACT
The human brain is a highly complex organ with remarkable energy demands. Although it represents only 2% of the total body weight, it accounts for 20% of all oxygen consumption, reflecting its high rate of metabolic activity. Mitochondria have a crucial role in the supply of energy to the brain. Consequently, their deterioration can have important detrimental consequences on the function and plasticity of neurons, and is thought to have a pivotal role in ageing and in the pathogenesis of several neurological disorders. Owing to their inherent physiological functions, mitochondria are subjected to particularly high levels of stress and have evolved specific molecular quality-control mechanisms to maintain the mitochondrial components. Here, we review some of the most recent advances in the understanding of mitochondrial stress-control pathways, with a particular focus on how defects in such pathways might contribute to neurodegenerative disease.

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Role of Htt protein in mitochondrial trafficking and dynamics.              Mitochondrial movement in neurons is highly diverse and complex. Normal Htt protein              regulates anterograde (away from the cell body) and retrograde (towards the cell body)              transport of mitochondria by interacting with several trafficking mediators. Htt              stimulates trafficking by binding to HAP1, which in turn, leads to interaction with              the motor proteins dynein–dynactin and kinesin. Phosphorylation of Htt acts              as a molecular switch for anterograde versus retrograde mitochondrial transport. When              Htt is phosphorylated, kinesin-1 is recruited and promotes anterograde transport;              conversely, when Htt is unphosphorylated, kinesin-1 detaches from the motor complex              and induces a switch to retrograde transport (Ref. 95). In addition to migration and movement, mitochondria undergo cycles of              fusion and fission. The key mitochondrial fission regulator is dynamin-related protein              1 (DRP1). Similarly to dynamin, DRP1 seems to act as a mechano-enzyme to constrict and              divide mitochondria. Given that Htt interacts with dynamin, one can speculate that Htt              might regulate fission by interacting with DRP1. Abbreviations: HAP1, Htt-associated              protein 1; Htt, Huntingtin protein; P, phosphate.
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fig05: Role of Htt protein in mitochondrial trafficking and dynamics. Mitochondrial movement in neurons is highly diverse and complex. Normal Htt protein regulates anterograde (away from the cell body) and retrograde (towards the cell body) transport of mitochondria by interacting with several trafficking mediators. Htt stimulates trafficking by binding to HAP1, which in turn, leads to interaction with the motor proteins dynein–dynactin and kinesin. Phosphorylation of Htt acts as a molecular switch for anterograde versus retrograde mitochondrial transport. When Htt is phosphorylated, kinesin-1 is recruited and promotes anterograde transport; conversely, when Htt is unphosphorylated, kinesin-1 detaches from the motor complex and induces a switch to retrograde transport (Ref. 95). In addition to migration and movement, mitochondria undergo cycles of fusion and fission. The key mitochondrial fission regulator is dynamin-related protein 1 (DRP1). Similarly to dynamin, DRP1 seems to act as a mechano-enzyme to constrict and divide mitochondria. Given that Htt interacts with dynamin, one can speculate that Htt might regulate fission by interacting with DRP1. Abbreviations: HAP1, Htt-associated protein 1; Htt, Huntingtin protein; P, phosphate.

Mentions: Although the transcriptional deregulation of mtHtt is of great relevance, it cannot fully explain all the mitochondrial defects observed in HD. Recent studies indicate that impaired mitochondrial trafficking along axons and dendrites might also have an important role in the disease pathology (see Ref. 30 for a review). Mitochondria are dynamically transported along lengthy neuronal processes to provide energy to nerve terminals and maintain the normal neuronal function. ATP-dependent motor proteins regulate such mitochondrial movement: kinesins mediate anterograde transport (away from the cell body), and dynein-dynactin regulates retrograde transport (toward the cell body) (Ref. 92). Wild-type Htt seems to regulate the trafficking of endocytic vesicles by binding to Htt-associated protein 1 (HAP1) (see Ref. 30 for a review). This protein complex might act as a docking platform that interacts with the molecular motor dynein–dynactin and kinesin, and it is known to regulate microtubule-mediated BDNF (brain-derived neurotrophic factor) vesicle and mitochondrial transport (Refs 93, 94). Furthermore, phosphorylation of Htt seems to act as a molecular switch for bidirectional transport in neurons (Ref. 95) (Fig. 5). Figure 5


Mitochondrial quality control and neurological disease: an emerging connection.

de Castro IP, Martins LM, Tufi R - Expert Rev Mol Med (2010)

Role of Htt protein in mitochondrial trafficking and dynamics.              Mitochondrial movement in neurons is highly diverse and complex. Normal Htt protein              regulates anterograde (away from the cell body) and retrograde (towards the cell body)              transport of mitochondria by interacting with several trafficking mediators. Htt              stimulates trafficking by binding to HAP1, which in turn, leads to interaction with              the motor proteins dynein–dynactin and kinesin. Phosphorylation of Htt acts              as a molecular switch for anterograde versus retrograde mitochondrial transport. When              Htt is phosphorylated, kinesin-1 is recruited and promotes anterograde transport;              conversely, when Htt is unphosphorylated, kinesin-1 detaches from the motor complex              and induces a switch to retrograde transport (Ref. 95). In addition to migration and movement, mitochondria undergo cycles of              fusion and fission. The key mitochondrial fission regulator is dynamin-related protein              1 (DRP1). Similarly to dynamin, DRP1 seems to act as a mechano-enzyme to constrict and              divide mitochondria. Given that Htt interacts with dynamin, one can speculate that Htt              might regulate fission by interacting with DRP1. Abbreviations: HAP1, Htt-associated              protein 1; Htt, Huntingtin protein; P, phosphate.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2871738&req=5

fig05: Role of Htt protein in mitochondrial trafficking and dynamics. Mitochondrial movement in neurons is highly diverse and complex. Normal Htt protein regulates anterograde (away from the cell body) and retrograde (towards the cell body) transport of mitochondria by interacting with several trafficking mediators. Htt stimulates trafficking by binding to HAP1, which in turn, leads to interaction with the motor proteins dynein–dynactin and kinesin. Phosphorylation of Htt acts as a molecular switch for anterograde versus retrograde mitochondrial transport. When Htt is phosphorylated, kinesin-1 is recruited and promotes anterograde transport; conversely, when Htt is unphosphorylated, kinesin-1 detaches from the motor complex and induces a switch to retrograde transport (Ref. 95). In addition to migration and movement, mitochondria undergo cycles of fusion and fission. The key mitochondrial fission regulator is dynamin-related protein 1 (DRP1). Similarly to dynamin, DRP1 seems to act as a mechano-enzyme to constrict and divide mitochondria. Given that Htt interacts with dynamin, one can speculate that Htt might regulate fission by interacting with DRP1. Abbreviations: HAP1, Htt-associated protein 1; Htt, Huntingtin protein; P, phosphate.
Mentions: Although the transcriptional deregulation of mtHtt is of great relevance, it cannot fully explain all the mitochondrial defects observed in HD. Recent studies indicate that impaired mitochondrial trafficking along axons and dendrites might also have an important role in the disease pathology (see Ref. 30 for a review). Mitochondria are dynamically transported along lengthy neuronal processes to provide energy to nerve terminals and maintain the normal neuronal function. ATP-dependent motor proteins regulate such mitochondrial movement: kinesins mediate anterograde transport (away from the cell body), and dynein-dynactin regulates retrograde transport (toward the cell body) (Ref. 92). Wild-type Htt seems to regulate the trafficking of endocytic vesicles by binding to Htt-associated protein 1 (HAP1) (see Ref. 30 for a review). This protein complex might act as a docking platform that interacts with the molecular motor dynein–dynactin and kinesin, and it is known to regulate microtubule-mediated BDNF (brain-derived neurotrophic factor) vesicle and mitochondrial transport (Refs 93, 94). Furthermore, phosphorylation of Htt seems to act as a molecular switch for bidirectional transport in neurons (Ref. 95) (Fig. 5). Figure 5

Bottom Line: Mitochondria have a crucial role in the supply of energy to the brain.Consequently, their deterioration can have important detrimental consequences on the function and plasticity of neurons, and is thought to have a pivotal role in ageing and in the pathogenesis of several neurological disorders.Owing to their inherent physiological functions, mitochondria are subjected to particularly high levels of stress and have evolved specific molecular quality-control mechanisms to maintain the mitochondrial components.

View Article: PubMed Central - PubMed

Affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.

ABSTRACT
The human brain is a highly complex organ with remarkable energy demands. Although it represents only 2% of the total body weight, it accounts for 20% of all oxygen consumption, reflecting its high rate of metabolic activity. Mitochondria have a crucial role in the supply of energy to the brain. Consequently, their deterioration can have important detrimental consequences on the function and plasticity of neurons, and is thought to have a pivotal role in ageing and in the pathogenesis of several neurological disorders. Owing to their inherent physiological functions, mitochondria are subjected to particularly high levels of stress and have evolved specific molecular quality-control mechanisms to maintain the mitochondrial components. Here, we review some of the most recent advances in the understanding of mitochondrial stress-control pathways, with a particular focus on how defects in such pathways might contribute to neurodegenerative disease.

Show MeSH
Related in: MedlinePlus