Limits...
Ultrastructural studies of ALS mitochondria connect altered function and permeability with defects of mitophagy and mitochondriogenesis.

Ruffoli R, Bartalucci A, Frati A, Fornai F - Front Cell Neurosci (2015)

Bottom Line: In fact, it was recently indicated that a pathological mitophagy, mitochondriogenesis and calcium homeostasis produce different ultrastructural effects within specific regions of motor neurons.It is now evident that altered calcium buffering is compartment-dependent, as well as mitophagy and mitochondriogenesis.At the same time, the compartmentalization of such dysfunctions may be explained considering the compartments of calcium dynamics and autophagy flux within motor neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Pisa, Italy.

ABSTRACT
The key role of mitochondria in patients affected by amyotrophic lateral sclerosis (ALS) is well documented by electron microscopy studies of motor neurons within spinal cord and brainstem. Nonetheless, recent studies challenged the role of mitochondria placed within the cell body of motor neuron. In fact, it was demonstrated that, despite preservation of mitochondria placed within this compartment, there is no increase in the lifespan of transgenic mouse models of ALS. Thus, the present mini-review comments on morphological findings of mitochondrial alterations in ALS patients in connection with novel findings about mitochondrial dynamics within various compartments of motor neurons. The latter issue was recently investigated in relationship with altered calcium homeostasis and autophagy, which affect mitochondria in ALS. In fact, it was recently indicated that a pathological mitophagy, mitochondriogenesis and calcium homeostasis produce different ultrastructural effects within specific regions of motor neurons. This might explain why specific compartments of motor neurons possess different thresholds to mitochondrial damage. In particular, it appears that motor axons represent the most sensitive compartment which undergoes the earliest and most severe alterations in the course of ALS. It is now evident that altered calcium buffering is compartment-dependent, as well as mitophagy and mitochondriogenesis. On the other hand, mitochondrial homeostasis strongly relies on calcium handling, the removal of altered mitochondria through the autophagy flux (mitophagy) and the biogenesis of novel mitochondria (mitochondriogenesis). Thus, recent findings related to altered calcium storage and impaired autophagy flux in ALS may help to understand the occurrence of mitochondrial alterations as a hallmark in ALS patients. At the same time, the compartmentalization of such dysfunctions may be explained considering the compartments of calcium dynamics and autophagy flux within motor neurons.

No MeSH data available.


Related in: MedlinePlus

Paradigm of severe mitochondrial alterations in ALS motor neurons. The first (A–C) and the second column (D–F) show at low and high magnification, respectively, the severe damage produced to mitochondria by the SOD1 G93A ALS-inducing mutation. On the right column (G–I), the beneficial effects of autophagy, induced by lithium, are evident. Scale bars: A–C = 0.12 μm; D = 0.55 μm; E = 0.15 μm; F = 0.13 μm; G–I = 0.12 μm; from Fornai et al. (2008a), Supporting Information, SI Figure 21; Copyright (2008) National Academy of Sciences, USA.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4555074&req=5

Figure 1: Paradigm of severe mitochondrial alterations in ALS motor neurons. The first (A–C) and the second column (D–F) show at low and high magnification, respectively, the severe damage produced to mitochondria by the SOD1 G93A ALS-inducing mutation. On the right column (G–I), the beneficial effects of autophagy, induced by lithium, are evident. Scale bars: A–C = 0.12 μm; D = 0.55 μm; E = 0.15 μm; F = 0.13 μm; G–I = 0.12 μm; from Fornai et al. (2008a), Supporting Information, SI Figure 21; Copyright (2008) National Academy of Sciences, USA.

Mentions: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder, which is characterized by massive motor neuron loss in the brainstem and spinal cord as well as motor cortex (Charcot, 1874; Boillée et al., 2006). The severity of this neurological disorder led to intense research efforts aimed to elucidate molecular and cellular events underlying motor neuron degeneration. In dissecting the variety of molecular mechanisms which characterize ALS several experimental approaches have been used. Multiple pathways might play a detrimental role on motor neuron survival. In fact, at mitochondrial level the occurrence of altered calcium homeostasis was described in great detail by recent studies (Fuchs et al., 2013; Barrett et al., 2014), while at cellular level the evidence of altered autophagy machinery seems to be well established (Pasquali et al., 2009). Nonetheless, a final common pathway connecting fine molecular mechanisms within mitochondria and pathological events at cellular level still needs to be clarified. Therefore, in the present short manuscript we discuss the significance of ultrastructural evidence, which was established in ALS patients for decades, in connection with altered mechanisms of calcium homeostasis and mitochondrial dynamics. Mitochondrial alterations were described in the ultrastructural pathology of ALS since early 80’s by Atsumi (1981) when analyzing muscle biopsies from ALS patients. Despite their pioneer nature, these studies evidenced the earlier site of mitochondrial alterations at the level of muscle nerve endings. In fact, the routine description of motor neuron cell bodies carried out within ALS spinal cord, despite disclosing some hallmarks of ALS, rules out the potential role of ultrastructural pathology which occurs in motor nerve endings. In keeping with this, some authors emphasized mitochondrial alterations occurring within muscle nerve endings as key mechanisms of disease. Thus, Siklós et al. (1996) pointed out that, at early disease stages, ALS patients develop severe ultrastructural alterations within muscle presynaptic nerve terminals. This is known to consist of increased mitochondrial volume produced by dilution of the matrix and swelling of the organelles featuring broken cristae. These abnormalities represent a hallmark of ultrastructural pathology in ALS where giant mitochondria are often placed within big stagnant vesicular bodies, which were later identified as defective autophagy vacuoles. Remarkably, these findings in ALS patients are replicated by a number of ALS models (Sasaki and Iwata, 1996a,b, 2007; Fornai et al., 2008b; Ferrucci et al., 2010). Therefore, these models provided a useful tool to analyze the neurobiology of disease. For instance, it was established that giant mitochondria are associated with increased neuronal volume (Martin et al., 2007; Fornai et al., 2008a). Again, motor neuron cell body in ALS is filled with giant vesicles (Martin et al., 2007; Fornai et al., 2008a; Laird et al., 2008; see Figure 1). Not surprisingly, these giant vesicles may contain swollen and disrupted mitochondria (Fornai et al., 2008a). These vesicles often fill the whole cell body of motor neurons leading to the concept of slow necrosis (Martin et al., 2007). These vesicles stain for specific autophagy antigens indicating that autophagy pathway is often relented and/or impaired within ALS motor neurons (Fornai et al., 2008a; Laird et al., 2008). The autophagy machinery possesses a specific role in removing altered mitochondria (so-called mitophagy) which suggests that, apart from primary mitochondrial alterations, even a relented removal of aged/altered mitochondria co-exists to produce an overloading of dysfunctional mitochondria within motor neurons.


Ultrastructural studies of ALS mitochondria connect altered function and permeability with defects of mitophagy and mitochondriogenesis.

Ruffoli R, Bartalucci A, Frati A, Fornai F - Front Cell Neurosci (2015)

Paradigm of severe mitochondrial alterations in ALS motor neurons. The first (A–C) and the second column (D–F) show at low and high magnification, respectively, the severe damage produced to mitochondria by the SOD1 G93A ALS-inducing mutation. On the right column (G–I), the beneficial effects of autophagy, induced by lithium, are evident. Scale bars: A–C = 0.12 μm; D = 0.55 μm; E = 0.15 μm; F = 0.13 μm; G–I = 0.12 μm; from Fornai et al. (2008a), Supporting Information, SI Figure 21; Copyright (2008) National Academy of Sciences, USA.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555074&req=5

Figure 1: Paradigm of severe mitochondrial alterations in ALS motor neurons. The first (A–C) and the second column (D–F) show at low and high magnification, respectively, the severe damage produced to mitochondria by the SOD1 G93A ALS-inducing mutation. On the right column (G–I), the beneficial effects of autophagy, induced by lithium, are evident. Scale bars: A–C = 0.12 μm; D = 0.55 μm; E = 0.15 μm; F = 0.13 μm; G–I = 0.12 μm; from Fornai et al. (2008a), Supporting Information, SI Figure 21; Copyright (2008) National Academy of Sciences, USA.
Mentions: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder, which is characterized by massive motor neuron loss in the brainstem and spinal cord as well as motor cortex (Charcot, 1874; Boillée et al., 2006). The severity of this neurological disorder led to intense research efforts aimed to elucidate molecular and cellular events underlying motor neuron degeneration. In dissecting the variety of molecular mechanisms which characterize ALS several experimental approaches have been used. Multiple pathways might play a detrimental role on motor neuron survival. In fact, at mitochondrial level the occurrence of altered calcium homeostasis was described in great detail by recent studies (Fuchs et al., 2013; Barrett et al., 2014), while at cellular level the evidence of altered autophagy machinery seems to be well established (Pasquali et al., 2009). Nonetheless, a final common pathway connecting fine molecular mechanisms within mitochondria and pathological events at cellular level still needs to be clarified. Therefore, in the present short manuscript we discuss the significance of ultrastructural evidence, which was established in ALS patients for decades, in connection with altered mechanisms of calcium homeostasis and mitochondrial dynamics. Mitochondrial alterations were described in the ultrastructural pathology of ALS since early 80’s by Atsumi (1981) when analyzing muscle biopsies from ALS patients. Despite their pioneer nature, these studies evidenced the earlier site of mitochondrial alterations at the level of muscle nerve endings. In fact, the routine description of motor neuron cell bodies carried out within ALS spinal cord, despite disclosing some hallmarks of ALS, rules out the potential role of ultrastructural pathology which occurs in motor nerve endings. In keeping with this, some authors emphasized mitochondrial alterations occurring within muscle nerve endings as key mechanisms of disease. Thus, Siklós et al. (1996) pointed out that, at early disease stages, ALS patients develop severe ultrastructural alterations within muscle presynaptic nerve terminals. This is known to consist of increased mitochondrial volume produced by dilution of the matrix and swelling of the organelles featuring broken cristae. These abnormalities represent a hallmark of ultrastructural pathology in ALS where giant mitochondria are often placed within big stagnant vesicular bodies, which were later identified as defective autophagy vacuoles. Remarkably, these findings in ALS patients are replicated by a number of ALS models (Sasaki and Iwata, 1996a,b, 2007; Fornai et al., 2008b; Ferrucci et al., 2010). Therefore, these models provided a useful tool to analyze the neurobiology of disease. For instance, it was established that giant mitochondria are associated with increased neuronal volume (Martin et al., 2007; Fornai et al., 2008a). Again, motor neuron cell body in ALS is filled with giant vesicles (Martin et al., 2007; Fornai et al., 2008a; Laird et al., 2008; see Figure 1). Not surprisingly, these giant vesicles may contain swollen and disrupted mitochondria (Fornai et al., 2008a). These vesicles often fill the whole cell body of motor neurons leading to the concept of slow necrosis (Martin et al., 2007). These vesicles stain for specific autophagy antigens indicating that autophagy pathway is often relented and/or impaired within ALS motor neurons (Fornai et al., 2008a; Laird et al., 2008). The autophagy machinery possesses a specific role in removing altered mitochondria (so-called mitophagy) which suggests that, apart from primary mitochondrial alterations, even a relented removal of aged/altered mitochondria co-exists to produce an overloading of dysfunctional mitochondria within motor neurons.

Bottom Line: In fact, it was recently indicated that a pathological mitophagy, mitochondriogenesis and calcium homeostasis produce different ultrastructural effects within specific regions of motor neurons.It is now evident that altered calcium buffering is compartment-dependent, as well as mitophagy and mitochondriogenesis.At the same time, the compartmentalization of such dysfunctions may be explained considering the compartments of calcium dynamics and autophagy flux within motor neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa Pisa, Italy.

ABSTRACT
The key role of mitochondria in patients affected by amyotrophic lateral sclerosis (ALS) is well documented by electron microscopy studies of motor neurons within spinal cord and brainstem. Nonetheless, recent studies challenged the role of mitochondria placed within the cell body of motor neuron. In fact, it was demonstrated that, despite preservation of mitochondria placed within this compartment, there is no increase in the lifespan of transgenic mouse models of ALS. Thus, the present mini-review comments on morphological findings of mitochondrial alterations in ALS patients in connection with novel findings about mitochondrial dynamics within various compartments of motor neurons. The latter issue was recently investigated in relationship with altered calcium homeostasis and autophagy, which affect mitochondria in ALS. In fact, it was recently indicated that a pathological mitophagy, mitochondriogenesis and calcium homeostasis produce different ultrastructural effects within specific regions of motor neurons. This might explain why specific compartments of motor neurons possess different thresholds to mitochondrial damage. In particular, it appears that motor axons represent the most sensitive compartment which undergoes the earliest and most severe alterations in the course of ALS. It is now evident that altered calcium buffering is compartment-dependent, as well as mitophagy and mitochondriogenesis. On the other hand, mitochondrial homeostasis strongly relies on calcium handling, the removal of altered mitochondria through the autophagy flux (mitophagy) and the biogenesis of novel mitochondria (mitochondriogenesis). Thus, recent findings related to altered calcium storage and impaired autophagy flux in ALS may help to understand the occurrence of mitochondrial alterations as a hallmark in ALS patients. At the same time, the compartmentalization of such dysfunctions may be explained considering the compartments of calcium dynamics and autophagy flux within motor neurons.

No MeSH data available.


Related in: MedlinePlus