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Morphological and bioenergetic demands underlying the mitophagy in post-mitotic neurons: the pink-parkin pathway.

Amadoro G, Corsetti V, Florenzano F, Atlante A, Bobba A, Nicolin V, Nori SL, Calissano P - Front Aging Neurosci (2014)

Bottom Line: Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis.Contrary to replicating mammalian cells with a metabolism essentially glycolytic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs.Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.

View Article: PubMed Central - PubMed

Affiliation: Institute of Translational Pharmacology - National Research Council Rome, Italy ; European Brain Research Institute Rome, Italy.

ABSTRACT
Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Contrary to replicating mammalian cells with a metabolism essentially glycolytic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs. Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.

No MeSH data available.


Related in: MedlinePlus

Cartoon illustrating the mitochondrial turnover which copes with the compartmentalized and distinct energetic requirements in the cell body, axon, and synaptic compartments of post-mitotic neurons. (A) In neurons, mitochondria travel long distances from the cell body out to distal dendritic and axonal terminals, where they subserve the ATP production and calcium homeostasis. The dynamic processes of biogenesis, fusion–fission regulate the mitochondrial function and quality control, by allowing them to adapt to spatial–temporal changes in cellular energy requirements. Selective autophagy begins with the nucleation of an isolation membrane (phagophore) which surrounds the damaged mitochondria to be degraded. RER could serve as membrane donors for autophagosome formation and the elongation of nascent double-membraned autophagic vesicle requires the coordinated assembly of Atg12–Atg5–Atg16L complex and LC3–PE conju-gates. (B) Newly formed autophagosomes move along microtubules in two directions – as a result of the opposing activities of the minus-end-directed motor protein dynein/dynactin and a plus-end-directed motor kinesin – and, finally, concentrate in perinuclear region (close to centrosome) where fuse with the lysosomes. Degradation of autophagosomal mitochondrial cargoes is then achieved by the acid hydrolases and the cathepsin proteases that are present in the lysosomal lumen.
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Figure 4: Cartoon illustrating the mitochondrial turnover which copes with the compartmentalized and distinct energetic requirements in the cell body, axon, and synaptic compartments of post-mitotic neurons. (A) In neurons, mitochondria travel long distances from the cell body out to distal dendritic and axonal terminals, where they subserve the ATP production and calcium homeostasis. The dynamic processes of biogenesis, fusion–fission regulate the mitochondrial function and quality control, by allowing them to adapt to spatial–temporal changes in cellular energy requirements. Selective autophagy begins with the nucleation of an isolation membrane (phagophore) which surrounds the damaged mitochondria to be degraded. RER could serve as membrane donors for autophagosome formation and the elongation of nascent double-membraned autophagic vesicle requires the coordinated assembly of Atg12–Atg5–Atg16L complex and LC3–PE conju-gates. (B) Newly formed autophagosomes move along microtubules in two directions – as a result of the opposing activities of the minus-end-directed motor protein dynein/dynactin and a plus-end-directed motor kinesin – and, finally, concentrate in perinuclear region (close to centrosome) where fuse with the lysosomes. Degradation of autophagosomal mitochondrial cargoes is then achieved by the acid hydrolases and the cathepsin proteases that are present in the lysosomal lumen.

Mentions: A functional specialization into different sub-cellular compartments occurs in post-mitotic neurons since axon and dendrites, and not only the soma, exhibit unique biological and bioenergetic needs such as localized synthesis and degradation of proteins (Steward and Schuman, 2003; Piper and Holt, 2004). Furthermore axon and dendrites have each one their own specific transport mechanisms (Hirokawa et al., 2010; Namba et al., 2011), calcium regulation as well ER functions and localized ATP requirement (Hollenbeck and Saxton, 2005; Mironov, 2009; Wang and Schwarz, 2009; MacAskill and Kittler, 2010). Consequently, the regulation of mitochondrial turnover is more complex in neurons than in other mammalian non-neuronal cells because it has to provide for different sub-cellular compartments and locally regulate changeable concentrations of calcium and ADP (MacAskill et al., 2009; Mironov, 2009; Hirokawa et al., 2010; Cai et al., 2011; Figure 4). Synaptic activity (Rintoul et al., 2003; Sung et al., 2008), the levels of nitric oxide (NO; Zanelli et al., 2006) and calcium homeostasis, likely via the EF domains of Miro which operates as calcium sensor (MacAskill et al., 2009; Wang and Schwarz, 2009), tightly facilitate the trafficking and recruitment of neuronal mitochondria to high energy-demanding sub-compartments, such as dendrites and terminal fields. In response to the variable energy requirement of dendrites and axons, neuronal mitochondria can be locally anchored by interacting with neurofilament and neuron-specific intermediate filaments (Toh et al., 1980; Hirokawa and Takemura, 2005; Winter et al., 2008) or with microtubules via syntaphilin anchor (Kang et al., 2008). Interestingly, mitochondrial dynamics in axon and in distal dendrites of healthy post-mitotic neurons are less frequent of that observed in other non-neuronal cell or in cell bodies (Jendrach et al., 2005; Berman et al., 2009). This conclusion is supported by the fact that live-imaging quantifications show unexpectedly that in primary cultured neurons the process of fusion occurs in only 16% of mitochondria per hour in contrast to COS7 and INS1 cells where a fission event frequently occurs within 100 s after a coupled fusion (Twig et al., 2008). Furthermore, in highly polarized neurons, the mitochondrial fission/fusion balance is singularly regulated in different sub-cellular compartments depending on local energetic requirements in order to produce mainly elongated organelles in the somatodendritic compartment and more fragmented ones in distal axons (Overly et al., 1996; Popov et al., 2005). For instance synaptic mitochondria, which are localized at docking sites, significantly differ from other non-synaptic mitochondria as they are long-lived, undergo an increased oxidation during aging (Vos et al., 2010; Du et al., 2012) and contain higher levels of the matrix protein cyclophilin D which makes them more susceptible to calcium insult (Brown et al., 2006; Naga et al., 2007). These studies could also explain why the selective vulnerability of synapses (“dying-back” degeneration) is an early prominent characteristic of many human neurodegenerative disorders in which damage may begin at neuron terminals in the absence of any change in the cell body (Wishart et al., 2006; Bettini et al., 2007). Importantly, synaptic mitochondria are largely presynaptic (Gray and Whittaker, 1962; Nicholls, 1993) and residing mitochondria locally support the ATP synthesis and Ca2+ buffering in addition to the neurotransmitter synthesis and catabolism. Considering that (i) numerous neurodegenerative diseases are characterized by iron accumulation (Oshiro et al., 2011) which plays a crucial role in NMDA/NO-mediated neurotoxicity (Cheah et al., 2006; Chen et al., 2013); (ii) iron chelation is a strong Pink/parkin-independent activator of mitophagy (Allen et al., 2013), it has been proposed that an umbalance in homeostasis of this ion might affect in neurons the mitochondrial quality control processes (Allen et al., 2013). Interestingly, using primary cortical neurons which are chronically exposed to non-lethal low-concentration of rotenone, it has been proved that mitochondrial dynamics can be differentially affected in neurons over time and in specific sub-cellular regions. In fact, evidence outlines that the rates of fission and fusion of these organelles can modify during the in vitro cultures maturation (from 7 to 24 days of age) with changes which precede any sign of cell death, providing thus the existence of an important temporal window for new therapeutic opportunities prior to the onset of irreversible neurodegenerative phenomena. Besides, compartments-specific compensatory changes (i.e., homeostatic biogenesis) can be also possible in neurons in a attempt to balance the accumulating mitochondrial toxicity as demonstrated by the finding that the density of these organelles increases in more vulnerable and early affected distal neurites, prior to significant changes in cell bodies (Arnold et al., 2011). Furthermore, the morphology and function of ER, which plays a key role in mitochondrial fission (Friedman et al., 2011), may differ in somatodendritic compartment compared to distal axons (Ramírez and Couve, 2011) and the specialized sub-cellular contacts between ER and mitochondria [i.e., MAM (mitochondria-associated ER membrane)] involved in lipid synthesis and Ca2+ handling are also localized in hippocampal neurons at synapses to sustain locally their integrative activities and integrity (Hedskog et al., 2013). Finally, mitochondrial biogenesis occurs in neurons mainly in the soma (Davis and Clayton, 1996; Saxton and Hollenbeck, 2012) and the activation of its regulatory nuclear transcription factors – such as peroxisome proliferator-activated receptor gamma coactivator 1α (PPARGC1A/PGC-1α) and NFR-1/2 is controlled by neuronal activity (Yang et al., 2006; Scarpulla, 2008).


Morphological and bioenergetic demands underlying the mitophagy in post-mitotic neurons: the pink-parkin pathway.

Amadoro G, Corsetti V, Florenzano F, Atlante A, Bobba A, Nicolin V, Nori SL, Calissano P - Front Aging Neurosci (2014)

Cartoon illustrating the mitochondrial turnover which copes with the compartmentalized and distinct energetic requirements in the cell body, axon, and synaptic compartments of post-mitotic neurons. (A) In neurons, mitochondria travel long distances from the cell body out to distal dendritic and axonal terminals, where they subserve the ATP production and calcium homeostasis. The dynamic processes of biogenesis, fusion–fission regulate the mitochondrial function and quality control, by allowing them to adapt to spatial–temporal changes in cellular energy requirements. Selective autophagy begins with the nucleation of an isolation membrane (phagophore) which surrounds the damaged mitochondria to be degraded. RER could serve as membrane donors for autophagosome formation and the elongation of nascent double-membraned autophagic vesicle requires the coordinated assembly of Atg12–Atg5–Atg16L complex and LC3–PE conju-gates. (B) Newly formed autophagosomes move along microtubules in two directions – as a result of the opposing activities of the minus-end-directed motor protein dynein/dynactin and a plus-end-directed motor kinesin – and, finally, concentrate in perinuclear region (close to centrosome) where fuse with the lysosomes. Degradation of autophagosomal mitochondrial cargoes is then achieved by the acid hydrolases and the cathepsin proteases that are present in the lysosomal lumen.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927396&req=5

Figure 4: Cartoon illustrating the mitochondrial turnover which copes with the compartmentalized and distinct energetic requirements in the cell body, axon, and synaptic compartments of post-mitotic neurons. (A) In neurons, mitochondria travel long distances from the cell body out to distal dendritic and axonal terminals, where they subserve the ATP production and calcium homeostasis. The dynamic processes of biogenesis, fusion–fission regulate the mitochondrial function and quality control, by allowing them to adapt to spatial–temporal changes in cellular energy requirements. Selective autophagy begins with the nucleation of an isolation membrane (phagophore) which surrounds the damaged mitochondria to be degraded. RER could serve as membrane donors for autophagosome formation and the elongation of nascent double-membraned autophagic vesicle requires the coordinated assembly of Atg12–Atg5–Atg16L complex and LC3–PE conju-gates. (B) Newly formed autophagosomes move along microtubules in two directions – as a result of the opposing activities of the minus-end-directed motor protein dynein/dynactin and a plus-end-directed motor kinesin – and, finally, concentrate in perinuclear region (close to centrosome) where fuse with the lysosomes. Degradation of autophagosomal mitochondrial cargoes is then achieved by the acid hydrolases and the cathepsin proteases that are present in the lysosomal lumen.
Mentions: A functional specialization into different sub-cellular compartments occurs in post-mitotic neurons since axon and dendrites, and not only the soma, exhibit unique biological and bioenergetic needs such as localized synthesis and degradation of proteins (Steward and Schuman, 2003; Piper and Holt, 2004). Furthermore axon and dendrites have each one their own specific transport mechanisms (Hirokawa et al., 2010; Namba et al., 2011), calcium regulation as well ER functions and localized ATP requirement (Hollenbeck and Saxton, 2005; Mironov, 2009; Wang and Schwarz, 2009; MacAskill and Kittler, 2010). Consequently, the regulation of mitochondrial turnover is more complex in neurons than in other mammalian non-neuronal cells because it has to provide for different sub-cellular compartments and locally regulate changeable concentrations of calcium and ADP (MacAskill et al., 2009; Mironov, 2009; Hirokawa et al., 2010; Cai et al., 2011; Figure 4). Synaptic activity (Rintoul et al., 2003; Sung et al., 2008), the levels of nitric oxide (NO; Zanelli et al., 2006) and calcium homeostasis, likely via the EF domains of Miro which operates as calcium sensor (MacAskill et al., 2009; Wang and Schwarz, 2009), tightly facilitate the trafficking and recruitment of neuronal mitochondria to high energy-demanding sub-compartments, such as dendrites and terminal fields. In response to the variable energy requirement of dendrites and axons, neuronal mitochondria can be locally anchored by interacting with neurofilament and neuron-specific intermediate filaments (Toh et al., 1980; Hirokawa and Takemura, 2005; Winter et al., 2008) or with microtubules via syntaphilin anchor (Kang et al., 2008). Interestingly, mitochondrial dynamics in axon and in distal dendrites of healthy post-mitotic neurons are less frequent of that observed in other non-neuronal cell or in cell bodies (Jendrach et al., 2005; Berman et al., 2009). This conclusion is supported by the fact that live-imaging quantifications show unexpectedly that in primary cultured neurons the process of fusion occurs in only 16% of mitochondria per hour in contrast to COS7 and INS1 cells where a fission event frequently occurs within 100 s after a coupled fusion (Twig et al., 2008). Furthermore, in highly polarized neurons, the mitochondrial fission/fusion balance is singularly regulated in different sub-cellular compartments depending on local energetic requirements in order to produce mainly elongated organelles in the somatodendritic compartment and more fragmented ones in distal axons (Overly et al., 1996; Popov et al., 2005). For instance synaptic mitochondria, which are localized at docking sites, significantly differ from other non-synaptic mitochondria as they are long-lived, undergo an increased oxidation during aging (Vos et al., 2010; Du et al., 2012) and contain higher levels of the matrix protein cyclophilin D which makes them more susceptible to calcium insult (Brown et al., 2006; Naga et al., 2007). These studies could also explain why the selective vulnerability of synapses (“dying-back” degeneration) is an early prominent characteristic of many human neurodegenerative disorders in which damage may begin at neuron terminals in the absence of any change in the cell body (Wishart et al., 2006; Bettini et al., 2007). Importantly, synaptic mitochondria are largely presynaptic (Gray and Whittaker, 1962; Nicholls, 1993) and residing mitochondria locally support the ATP synthesis and Ca2+ buffering in addition to the neurotransmitter synthesis and catabolism. Considering that (i) numerous neurodegenerative diseases are characterized by iron accumulation (Oshiro et al., 2011) which plays a crucial role in NMDA/NO-mediated neurotoxicity (Cheah et al., 2006; Chen et al., 2013); (ii) iron chelation is a strong Pink/parkin-independent activator of mitophagy (Allen et al., 2013), it has been proposed that an umbalance in homeostasis of this ion might affect in neurons the mitochondrial quality control processes (Allen et al., 2013). Interestingly, using primary cortical neurons which are chronically exposed to non-lethal low-concentration of rotenone, it has been proved that mitochondrial dynamics can be differentially affected in neurons over time and in specific sub-cellular regions. In fact, evidence outlines that the rates of fission and fusion of these organelles can modify during the in vitro cultures maturation (from 7 to 24 days of age) with changes which precede any sign of cell death, providing thus the existence of an important temporal window for new therapeutic opportunities prior to the onset of irreversible neurodegenerative phenomena. Besides, compartments-specific compensatory changes (i.e., homeostatic biogenesis) can be also possible in neurons in a attempt to balance the accumulating mitochondrial toxicity as demonstrated by the finding that the density of these organelles increases in more vulnerable and early affected distal neurites, prior to significant changes in cell bodies (Arnold et al., 2011). Furthermore, the morphology and function of ER, which plays a key role in mitochondrial fission (Friedman et al., 2011), may differ in somatodendritic compartment compared to distal axons (Ramírez and Couve, 2011) and the specialized sub-cellular contacts between ER and mitochondria [i.e., MAM (mitochondria-associated ER membrane)] involved in lipid synthesis and Ca2+ handling are also localized in hippocampal neurons at synapses to sustain locally their integrative activities and integrity (Hedskog et al., 2013). Finally, mitochondrial biogenesis occurs in neurons mainly in the soma (Davis and Clayton, 1996; Saxton and Hollenbeck, 2012) and the activation of its regulatory nuclear transcription factors – such as peroxisome proliferator-activated receptor gamma coactivator 1α (PPARGC1A/PGC-1α) and NFR-1/2 is controlled by neuronal activity (Yang et al., 2006; Scarpulla, 2008).

Bottom Line: Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis.Contrary to replicating mammalian cells with a metabolism essentially glycolytic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs.Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.

View Article: PubMed Central - PubMed

Affiliation: Institute of Translational Pharmacology - National Research Council Rome, Italy ; European Brain Research Institute Rome, Italy.

ABSTRACT
Evidence suggests a striking causal relationship between changes in quality control of neuronal mitochondria and numerous devastating human neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Contrary to replicating mammalian cells with a metabolism essentially glycolytic, post-mitotic neurons are distinctive owing to (i) their exclusive energetic dependence from mitochondrial metabolism and (ii) their polarized shape, which entails compartmentalized and distinct energetic needs. Here, we review the recent findings on mitochondrial dynamics and mitophagy in differentiated neurons focusing on how the exceptional characteristics of neuronal populations in their morphology and bioenergetics needs make them quite different to other cells in controlling the intracellular turnover of these organelles.

No MeSH data available.


Related in: MedlinePlus