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  1. Chin-San Liu, Jui-Chih Chang, Shou-Jen Kuo, Ko-Hung Liu, Ta-Tsung Lin, Wen-Ling Cheng and Sheng-Fei Chuang.
    Delivering healthy mitochondria for the therapy of mitochondrial diseases and beyond.. The international journal of biochemistry & cell biology, May 2014.
    Abstract Mitochondrial transfer has been demonstrated to a play a physiological role in the rescuing of mitochondrial DNA deficient cells by co-culture with human mesenchymal stem cells. The successful replacement of mitochondria using microinjection into the embryo has been revealed to improve embryo maturation. Evidence of mitochondrial transfer has been shown to minimize injury of the ischemic-reperfusion rabbit heart model. In this mini review, the therapeutic strategies of mitochondrial diseases based on the concept of mitochondrial transfer are illustrated, as well as a novel approach to peptide-mediated mitochondrial delivery. The possible mechanism of peptide-mediated mitochondrial delivery in the treatment of the myoclonic epilepsy and ragged-red fiber disease is summarized. Understanding the feasibility of mitochondrial manipulation in cells facilitates novel therapeutic skills in the future clinical practice of mitochondrial disorder.
    URL, DOI BibTeX

    @article{Liu2014,
    	abstract = "Mitochondrial transfer has been demonstrated to a play a physiological role in the rescuing of mitochondrial DNA deficient cells by co-culture with human mesenchymal stem cells. The successful replacement of mitochondria using microinjection into the embryo has been revealed to improve embryo maturation. Evidence of mitochondrial transfer has been shown to minimize injury of the ischemic-reperfusion rabbit heart model. In this mini review, the therapeutic strategies of mitochondrial diseases based on the concept of mitochondrial transfer are illustrated, as well as a novel approach to peptide-mediated mitochondrial delivery. The possible mechanism of peptide-mediated mitochondrial delivery in the treatment of the myoclonic epilepsy and ragged-red fiber disease is summarized. Understanding the feasibility of mitochondrial manipulation in cells facilitates novel therapeutic skills in the future clinical practice of mitochondrial disorder.",
    	author = "Liu, Chin-San and Chang, Jui-Chih and Kuo, Shou-Jen and Liu, Ko-Hung and Lin, Ta-Tsung and Cheng, Wen-Ling and Chuang, Sheng-Fei",
    	doi = "10.1016/j.biocel.2014.05.009",
    	issn = "1878-5875",
    	journal = "The international journal of biochemistry \& cell biology",
    	month = "may",
    	pmid = 24842105,
    	title = "{Delivering healthy mitochondria for the therapy of mitochondrial diseases and beyond.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24842105",
    	year = 2014
    }
    
  2. Luz Diana Santa-Cruz and Ricardo Tapia.
    Role of energy metabolic deficits and oxidative stress in excitotoxic spinal motor neuron degeneration in vivo.. ASN neuro 6(2), January 2014.
    Abstract MN (motor neuron) death in amyotrophic lateral sclerosis may be mediated by glutamatergic excitotoxicity. Previously, our group showed that the microdialysis perfusion of AMPA ($\alpha$-amino-3-hydroxy-5-methyl-4-isoxazole propionate) in the rat lumbar spinal cord induced MN death and permanent paralysis within 12 h after the experiment. Here, we studied the involvement of energy metabolic deficiencies and of oxidative stress in this MN degeneration, by testing the neuroprotective effect of various energy metabolic substrates and antioxidants. Pyruvate, lactate, $\beta$-hydroxybutyrate, $\alpha$-ketobutyrate and creatine reduced MN loss by 50-65%, preserved motor function and completely prevented the paralysis. Ascorbate, glutathione and glutathione ethyl ester weakly protected against motor deficits and reduced MN death by only 30-40%. Reactive oxygen species formation and 3-nitrotyrosine immunoreactivity were studied 1.5-2 h after AMPA perfusion, during the initial MN degenerating process, and no changes were observed. We conclude that mitochondrial energy deficiency plays a crucial role in this excitotoxic spinal MN degeneration, whereas oxidative stress seems a less relevant mechanism. Interestingly, we observed a clear correlation between the alterations of motor function and the number of damaged MNs, suggesting that there is a threshold of about 50% in the number of healthy MNs necessary to preserve motor function.
    URL, DOI BibTeX

    @article{Santa-Cruz2014,
    	abstract = "MN (motor neuron) death in amyotrophic lateral sclerosis may be mediated by glutamatergic excitotoxicity. Previously, our group showed that the microdialysis perfusion of AMPA ($\alpha$-amino-3-hydroxy-5-methyl-4-isoxazole propionate) in the rat lumbar spinal cord induced MN death and permanent paralysis within 12 h after the experiment. Here, we studied the involvement of energy metabolic deficiencies and of oxidative stress in this MN degeneration, by testing the neuroprotective effect of various energy metabolic substrates and antioxidants. Pyruvate, lactate, $\beta$-hydroxybutyrate, $\alpha$-ketobutyrate and creatine reduced MN loss by 50-65\%, preserved motor function and completely prevented the paralysis. Ascorbate, glutathione and glutathione ethyl ester weakly protected against motor deficits and reduced MN death by only 30-40\%. Reactive oxygen species formation and 3-nitrotyrosine immunoreactivity were studied 1.5-2 h after AMPA perfusion, during the initial MN degenerating process, and no changes were observed. We conclude that mitochondrial energy deficiency plays a crucial role in this excitotoxic spinal MN degeneration, whereas oxidative stress seems a less relevant mechanism. Interestingly, we observed a clear correlation between the alterations of motor function and the number of damaged MNs, suggesting that there is a threshold of about 50\% in the number of healthy MNs necessary to preserve motor function.",
    	author = "Santa-Cruz, Luz Diana and Tapia, Ricardo",
    	doi = "10.1042/AN20130046",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Santa-Cruz, Tapia - 2014 - Role of energy metabolic deficits and oxidative stress in excitotoxic spinal motor neuron degeneration in viv.pdf:pdf",
    	issn = "1759-0914",
    	journal = "ASN neuro",
    	month = "jan",
    	number = 2,
    	pmid = 24524836,
    	title = "{Role of energy metabolic deficits and oxidative stress in excitotoxic spinal motor neuron degeneration in vivo.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3950966\&tool=pmcentrez\&rendertype=abstract",
    	volume = 6,
    	year = 2014
    }
    
  3. L D Osellame and M R Duchen.
    Quality control gone wrong: mitochondria, lysosomal storage disorders and neurodegeneration.. British journal of pharmacology 171(8):1958–72, 2014.
    Abstract The eukaryotic cell possesses specialized pathways to turn over and degrade redundant proteins and organelles. Each pathway is unique and responsible for degradation of distinctive cytosolic material. The ubiquitin-proteasome system and autophagy (chaperone-mediated, macro, micro and organelle specific) act synergistically to maintain proteostasis. Defects in this equilibrium can be deleterious at cellular and organism level, giving rise to various disease states. Dysfunction of quality control pathways are implicated in neurodegenerative diseases and appear particularly important in Parkinson's disease and the lysosomal storage disorders. Neurodegeneration resulting from impaired degradation of ubiquitinated proteins and $\alpha$-synuclein is often accompanied by mitochondrial dysfunction. Mitochondria have evolved to control a diverse number of processes, including cellular energy production, calcium signalling and apoptosis, and like every other organelle within the cell, they must be 'recycled.' Failure to do so is potentially lethal as these once indispensible organelles become destructive, leaking reactive oxygen species and activating the intrinsic cell death pathway. This process is paramount in neurons which have an absolute dependence on mitochondrial oxidative phosphorylation as they cannot up-regulate glycolysis. As such, mitochondrial bioenergetic failure can underpin neural death and neurodegenerative disease. In this review, we discuss the links between cellular quality control and neurodegenerative diseases associated with mitochondrial dysfunction, with particular attention to the emerging links between Parkinson's and Gaucher diseases in which defective quality control is a defining factor.
    URL, DOI BibTeX

    @article{Osellame2014,
    	abstract = "The eukaryotic cell possesses specialized pathways to turn over and degrade redundant proteins and organelles. Each pathway is unique and responsible for degradation of distinctive cytosolic material. The ubiquitin-proteasome system and autophagy (chaperone-mediated, macro, micro and organelle specific) act synergistically to maintain proteostasis. Defects in this equilibrium can be deleterious at cellular and organism level, giving rise to various disease states. Dysfunction of quality control pathways are implicated in neurodegenerative diseases and appear particularly important in Parkinson's disease and the lysosomal storage disorders. Neurodegeneration resulting from impaired degradation of ubiquitinated proteins and $\alpha$-synuclein is often accompanied by mitochondrial dysfunction. Mitochondria have evolved to control a diverse number of processes, including cellular energy production, calcium signalling and apoptosis, and like every other organelle within the cell, they must be 'recycled.' Failure to do so is potentially lethal as these once indispensible organelles become destructive, leaking reactive oxygen species and activating the intrinsic cell death pathway. This process is paramount in neurons which have an absolute dependence on mitochondrial oxidative phosphorylation as they cannot up-regulate glycolysis. As such, mitochondrial bioenergetic failure can underpin neural death and neurodegenerative disease. In this review, we discuss the links between cellular quality control and neurodegenerative diseases associated with mitochondrial dysfunction, with particular attention to the emerging links between Parkinson's and Gaucher diseases in which defective quality control is a defining factor.",
    	author = "Osellame, L D and Duchen, M R",
    	doi = "10.1111/bph.12453",
    	issn = "1476-5381",
    	journal = "British journal of pharmacology",
    	month = "",
    	number = 8,
    	pages = "1958--72",
    	pmid = 24116849,
    	title = "{Quality control gone wrong: mitochondria, lysosomal storage disorders and neurodegeneration.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24116849",
    	volume = 171,
    	year = 2014
    }
    
  4. Luc Dupuis.
    Mitochondrial quality control in neurodegenerative diseases.. Biochimie 100:177–83, 2014.
    Abstract Mutations causing genetic forms of Parkinson's disease or hereditary neuropathies have been recently shown to affect key molecular players involved in the recycling of defective mitochondria, most notably PARKIN, PINK1, Mitofusin 2 or dynein heavy chain. Interestingly, the same pathways are also indirectly targeted by multiple other mutations involved in familial forms of amyotrophic lateral sclerosis, Huntington's disease or Alzheimer's disease. These recent genetic results strongly reinforce the notion that defective mitochondrial physiology might cause neurodegeneration. Mitochondrial dysfunction has however been observed in virtually every neurodegenerative disease and appears not restricted to the most vulnerable neuronal populations affected by a given disease. Thus, the mechanisms linking defective mitochondrial quality control to death of selective neuronal populations remain to be identified. This review provides an update on the most recent literature on mitochondrial quality control and its impairment during neurodegenerative diseases.
    URL, DOI BibTeX

    @article{Dupuis2014,
    	abstract = "Mutations causing genetic forms of Parkinson's disease or hereditary neuropathies have been recently shown to affect key molecular players involved in the recycling of defective mitochondria, most notably PARKIN, PINK1, Mitofusin 2 or dynein heavy chain. Interestingly, the same pathways are also indirectly targeted by multiple other mutations involved in familial forms of amyotrophic lateral sclerosis, Huntington's disease or Alzheimer's disease. These recent genetic results strongly reinforce the notion that defective mitochondrial physiology might cause neurodegeneration. Mitochondrial dysfunction has however been observed in virtually every neurodegenerative disease and appears not restricted to the most vulnerable neuronal populations affected by a given disease. Thus, the mechanisms linking defective mitochondrial quality control to death of selective neuronal populations remain to be identified. This review provides an update on the most recent literature on mitochondrial quality control and its impairment during neurodegenerative diseases.",
    	author = "Dupuis, Luc",
    	doi = "10.1016/j.biochi.2013.07.033",
    	issn = "1638-6183",
    	journal = "Biochimie",
    	month = "",
    	pages = "177--83",
    	pmid = 23958438,
    	title = "{Mitochondrial quality control in neurodegenerative diseases.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23958438",
    	volume = 100,
    	year = 2014
    }
    
  5. Giuseppina Amadoro, Veronica Corsetti, Fulvio Florenzano, Anna Atlante, Antonella Bobba, Vanessa Nicolin, Stefania L Nori and Pietro Calissano.
    Morphological and bioenergetic demands underlying the mitophagy in post-mitotic neurons: the pink-parkin pathway.. Frontiers in aging neuroscience 6:18, 2014.
    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.
    URL, DOI BibTeX

    @article{Amadoro2014,
    	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.",
    	author = "Amadoro, Giuseppina and Corsetti, Veronica and Florenzano, Fulvio and Atlante, Anna and Bobba, Antonella and Nicolin, Vanessa and Nori, Stefania L and Calissano, Pietro",
    	doi = "10.3389/fnagi.2014.00018",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Amadoro et al. - 2014 - Morphological and bioenergetic demands underlying the mitophagy in post-mitotic neurons the pink-parkin pathway.pdf:pdf",
    	issn = "1663-4365",
    	journal = "Frontiers in aging neuroscience",
    	month = "",
    	pages = 18,
    	pmid = 24600391,
    	title = "{Morphological and bioenergetic demands underlying the mitophagy in post-mitotic neurons: the pink-parkin pathway.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3927396\&tool=pmcentrez\&rendertype=abstract",
    	volume = 6,
    	year = 2014
    }
    
  6. Wenzhang Wang, Li Li, Wen-Lang Lin, Dennis W Dickson, Leonard Petrucelli, Teng Zhang and Xinglong Wang.
    The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons.. Human molecular genetics 22(23):4706–19, December 2013.
    Abstract Mutations in TDP-43 lead to familial ALS. Expanding evidence suggests that impaired mitochondrial dynamics likely contribute to the selective degeneration of motor neurons in SOD1-associated ALS. In this study, we investigated whether and how TDP-43 mutations might impact mitochondrial dynamics and function. We demonstrated that overexpression of wild-type TDP-43 resulted in reduced mitochondrial length and density in neurites of primary motor neurons, features further exacerbated by ALS-associated TDP-43 mutants Q331K and M337V. In contrast, suppression of TDP-43 resulted in significantly increased mitochondrial length and density in neurites, suggesting a specific role of TDP-43 in regulating mitochondrial dynamics. Surprisingly, both TDP-43 overexpression and suppression impaired mitochondrial movement. We further showed that abnormal localization of TDP-43 in cytoplasm induced substantial and widespread abnormal mitochondrial dynamics. TDP-43 co-localized with mitochondria in motor neurons and their colocalization was enhanced by ALS associated mutant. Importantly, co-expression of mitochondrial fusion protein mitofusin 2 (Mfn2) could abolish TDP-43 induced mitochondrial dynamics abnormalities and mitochondrial dysfunction. Taken together, these data suggest that mutant TDP-43 impairs mitochondrial dynamics through enhanced localization on mitochondria, which causes mitochondrial dysfunction. Therefore, abnormal mitochondrial dynamics is likely a common feature of ALS which could be potential new therapeutic targets to treat ALS.
    URL, DOI BibTeX

    @article{Wang2013,
    	abstract = "Mutations in TDP-43 lead to familial ALS. Expanding evidence suggests that impaired mitochondrial dynamics likely contribute to the selective degeneration of motor neurons in SOD1-associated ALS. In this study, we investigated whether and how TDP-43 mutations might impact mitochondrial dynamics and function. We demonstrated that overexpression of wild-type TDP-43 resulted in reduced mitochondrial length and density in neurites of primary motor neurons, features further exacerbated by ALS-associated TDP-43 mutants Q331K and M337V. In contrast, suppression of TDP-43 resulted in significantly increased mitochondrial length and density in neurites, suggesting a specific role of TDP-43 in regulating mitochondrial dynamics. Surprisingly, both TDP-43 overexpression and suppression impaired mitochondrial movement. We further showed that abnormal localization of TDP-43 in cytoplasm induced substantial and widespread abnormal mitochondrial dynamics. TDP-43 co-localized with mitochondria in motor neurons and their colocalization was enhanced by ALS associated mutant. Importantly, co-expression of mitochondrial fusion protein mitofusin 2 (Mfn2) could abolish TDP-43 induced mitochondrial dynamics abnormalities and mitochondrial dysfunction. Taken together, these data suggest that mutant TDP-43 impairs mitochondrial dynamics through enhanced localization on mitochondria, which causes mitochondrial dysfunction. Therefore, abnormal mitochondrial dynamics is likely a common feature of ALS which could be potential new therapeutic targets to treat ALS.",
    	author = "Wang, Wenzhang and Li, Li and Lin, Wen-Lang and Dickson, Dennis W and Petrucelli, Leonard and Zhang, Teng and Wang, Xinglong",
    	doi = "10.1093/hmg/ddt319",
    	issn = "1460-2083",
    	journal = "Human molecular genetics",
    	month = "dec",
    	number = 23,
    	pages = "4706--19",
    	pmid = 23827948,
    	title = "{The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23827948",
    	volume = 22,
    	year = 2013
    }
    
  7. Parisa Ghiasi, Saman Hosseinkhani, Alireza Noori, Shahriar Nafissi and Khosro Khajeh.
    Mitochondrial complex I deficiency and ATP/ADP ratio in lymphocytes of amyotrophic lateral sclerosis patients.. Neurological research 34(3):297–303, April 2012.
    Abstract OBJECTIVES: Several lines of evidence suggest that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis (ALS), but despite the fact that mitochondria play a central role in excitotoxicity, oxidative stress, and apoptosis, the intimate underlying mechanism linking mitochondrial defects to motor neuron degeneration in ALS still remains elusive. This study was performed to assess the mitochondrial respiratory chain dysfunction and cellular energy index (ATP/ADP ratio) in lymphocytes of ALS patients. METHODS: In this study, activity of mitochondrial respiratory chain complex I (measured as NADH-ferricyanide reductase) and both intracellular ATP and ADP measurements were performed on lymphocytes of ALS patients (n = 14) and control subjects (n = 26). Then, ATP/ADP ratio was calculated. RESULTS: Our finding showed that in patients compared with controls, complex I activity and intracellular ATP were significantly reduced (P = 0·001) and intracellular ADP content was increased (P<0·005) and ATP/ADP ratio subsequently was decreased and also we found strong correlation between complex I activity and intracellular ATP content and strong reverse correlation between complex I activity and intracellular ADP content in the patients with ALS (r(2) = 0·90). DISCUSSION: This study suggests that complex I deficiency and both reduction in intracellular ATP and increase in intracellular ADP content may be involved in the progression and pathogenesis of ALS.
    URL, DOI BibTeX

    @article{Ghiasi2012,
    	abstract = "OBJECTIVES: Several lines of evidence suggest that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis (ALS), but despite the fact that mitochondria play a central role in excitotoxicity, oxidative stress, and apoptosis, the intimate underlying mechanism linking mitochondrial defects to motor neuron degeneration in ALS still remains elusive. This study was performed to assess the mitochondrial respiratory chain dysfunction and cellular energy index (ATP/ADP ratio) in lymphocytes of ALS patients. METHODS: In this study, activity of mitochondrial respiratory chain complex I (measured as NADH-ferricyanide reductase) and both intracellular ATP and ADP measurements were performed on lymphocytes of ALS patients (n = 14) and control subjects (n = 26). Then, ATP/ADP ratio was calculated. RESULTS: Our finding showed that in patients compared with controls, complex I activity and intracellular ATP were significantly reduced (P = 0·001) and intracellular ADP content was increased (P<0·005) and ATP/ADP ratio subsequently was decreased and also we found strong correlation between complex I activity and intracellular ATP content and strong reverse correlation between complex I activity and intracellular ADP content in the patients with ALS (r(2) = 0·90). DISCUSSION: This study suggests that complex I deficiency and both reduction in intracellular ATP and increase in intracellular ADP content may be involved in the progression and pathogenesis of ALS.",
    	author = "Ghiasi, Parisa and Hosseinkhani, Saman and Noori, Alireza and Nafissi, Shahriar and Khajeh, Khosro",
    	doi = "10.1179/1743132812Y.0000000012",
    	issn = "1743-1328",
    	journal = "Neurological research",
    	keywords = "Adenosine Diphosphate,Adenosine Diphosphate: analysis,Adenosine Diphosphate: metabolism,Adenosine Triphosphate,Adenosine Triphosphate: analysis,Adenosine Triphosphate: metabolism,Adult,Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Electron Transport Complex I,Electron Transport Complex I: deficiency,Female,Humans,Lymphocytes,Lymphocytes: chemistry,Lymphocytes: metabolism,Male,Middle Aged",
    	month = "apr",
    	number = 3,
    	pages = "297--303",
    	pmid = 22450425,
    	title = "{Mitochondrial complex I deficiency and ATP/ADP ratio in lymphocytes of amyotrophic lateral sclerosis patients.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22450425",
    	volume = 34,
    	year = 2012
    }
    
  8. Ernesto Miquel, Adriana Cassina, Laura Mart\'ınez-Palma, Carmen Bolatto, Emiliano Tr\'ıas, Mandi Gandelman, Rafael Radi, Luis Barbeito and Patricia Cassina.
    Modulation of astrocytic mitochondrial function by dichloroacetate improves survival and motor performance in inherited amyotrophic lateral sclerosis.. PloS one 7(4):e34776, January 2012.
    Abstract Mitochondrial dysfunction is one of the pathogenic mechanisms that lead to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). Astrocytes expressing the ALS-linked SOD1(G93A) mutation display a decreased mitochondrial respiratory capacity associated to phenotypic changes that cause them to induce motor neuron death. Astrocyte-mediated toxicity can be prevented by mitochondria-targeted antioxidants, indicating a critical role of mitochondria in the neurotoxic phenotype. However, it is presently unknown whether drugs currently used to stimulate mitochondrial metabolism can also modulate ALS progression. Here, we tested the disease-modifying effect of dichloroacetate (DCA), an orphan drug that improves the functional status of mitochondria through the stimulation of the pyruvate dehydrogenase complex activity (PDH). Applied to astrocyte cultures isolated from rats expressing the SOD1(G93A) mutation, DCA reduced phosphorylation of PDH and improved mitochondrial coupling as expressed by the respiratory control ratio (RCR). Notably, DCA completely prevented the toxicity of SOD1(G93A) astrocytes to motor neurons in coculture conditions. Chronic administration of DCA (500 mg/L) in the drinking water of mice expressing the SOD1(G93A) mutation increased survival by 2 weeks compared to untreated mice. Systemic DCA also normalized the reduced RCR value measured in lumbar spinal cord tissue of diseased SOD1(G93A) mice. A remarkable effect of DCA was the improvement of grip strength performance at the end stage of the disease, which correlated with a recovery of the neuromuscular junction area in extensor digitorum longus muscles. Systemic DCA also decreased astrocyte reactivity and prevented motor neuron loss in SOD1(G93A) mice. Taken together, our results indicate that improvement of the mitochondrial redox status by DCA leads to a disease-modifying effect, further supporting the therapeutic potential of mitochondria-targeted drugs in ALS.
    URL, DOI BibTeX

    @article{Miquel2012,
    	abstract = "Mitochondrial dysfunction is one of the pathogenic mechanisms that lead to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). Astrocytes expressing the ALS-linked SOD1(G93A) mutation display a decreased mitochondrial respiratory capacity associated to phenotypic changes that cause them to induce motor neuron death. Astrocyte-mediated toxicity can be prevented by mitochondria-targeted antioxidants, indicating a critical role of mitochondria in the neurotoxic phenotype. However, it is presently unknown whether drugs currently used to stimulate mitochondrial metabolism can also modulate ALS progression. Here, we tested the disease-modifying effect of dichloroacetate (DCA), an orphan drug that improves the functional status of mitochondria through the stimulation of the pyruvate dehydrogenase complex activity (PDH). Applied to astrocyte cultures isolated from rats expressing the SOD1(G93A) mutation, DCA reduced phosphorylation of PDH and improved mitochondrial coupling as expressed by the respiratory control ratio (RCR). Notably, DCA completely prevented the toxicity of SOD1(G93A) astrocytes to motor neurons in coculture conditions. Chronic administration of DCA (500 mg/L) in the drinking water of mice expressing the SOD1(G93A) mutation increased survival by 2 weeks compared to untreated mice. Systemic DCA also normalized the reduced RCR value measured in lumbar spinal cord tissue of diseased SOD1(G93A) mice. A remarkable effect of DCA was the improvement of grip strength performance at the end stage of the disease, which correlated with a recovery of the neuromuscular junction area in extensor digitorum longus muscles. Systemic DCA also decreased astrocyte reactivity and prevented motor neuron loss in SOD1(G93A) mice. Taken together, our results indicate that improvement of the mitochondrial redox status by DCA leads to a disease-modifying effect, further supporting the therapeutic potential of mitochondria-targeted drugs in ALS.",
    	author = "Miquel, Ernesto and Cassina, Adriana and Mart\'{\i}nez-Palma, Laura and Bolatto, Carmen and Tr\'{\i}as, Emiliano and Gandelman, Mandi and Radi, Rafael and Barbeito, Luis and Cassina, Patricia",
    	doi = "10.1371/journal.pone.0034776",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Miquel et al. - 2012 - Modulation of astrocytic mitochondrial function by dichloroacetate improves survival and motor performance in inh.pdf:pdf",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: drug therapy,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Animals,Astrocytes,Astrocytes: drug effects,Astrocytes: metabolism,Cell Death,Cell Death: drug effects,Cell Survival,Cell Survival: drug effects,Cells, Cultured,Dichloroacetic Acid,Dichloroacetic Acid: pharmacology,Disease Models, Animal,Female,Humans,Male,Mice,Mice, Transgenic,Mitochondria,Mitochondria: drug effects,Mitochondria: physiology,Motor Neurons,Motor Neurons: drug effects,Oxidation-Reduction,Oxidation-Reduction: drug effects,Phosphorylation,Phosphorylation: drug effects,Pyruvate Dehydrogenase Complex,Pyruvate Dehydrogenase Complex: metabolism,Rats,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism",
    	month = "jan",
    	number = 4,
    	pages = "e34776",
    	pmid = 22509356,
    	title = "{Modulation of astrocytic mitochondrial function by dichloroacetate improves survival and motor performance in inherited amyotrophic lateral sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3318006\&tool=pmcentrez\&rendertype=abstract",
    	volume = 7,
    	year = 2012
    }
    
  9. Liesbeth Faes and Geert Callewaert.
    Mitochondrial dysfunction in familial amyotrophic lateral sclerosis.. Journal of bioenergetics and biomembranes 43(6):587–92, 2011.
    Abstract A growing body of evidence suggests that mitochondrial dysfunctions play a crucial role in the pathogenesis of various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting both upper and lower motor neurons. Although ALS is predominantly a sporadic disease, approximately 10% of cases are familial. The most frequent familial form is caused by mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD1). A dominant toxic gain of function of mutant SOD1 has been considered as the cause of the disease and mitochondria are thought to be key players in the pathogenesis. However, the exact nature of the link between mutant SOD1 and mitochondrial dysfunctions remains to be established. Here, we briefly review the evidence for mitochondrial dysfunctions in familial ALS and discuss a possible link between mutant SOD1 and mitochondrial dysfunction.
    URL, DOI BibTeX

    @article{Faes2011,
    	abstract = "A growing body of evidence suggests that mitochondrial dysfunctions play a crucial role in the pathogenesis of various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting both upper and lower motor neurons. Although ALS is predominantly a sporadic disease, approximately 10\% of cases are familial. The most frequent familial form is caused by mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD1). A dominant toxic gain of function of mutant SOD1 has been considered as the cause of the disease and mitochondria are thought to be key players in the pathogenesis. However, the exact nature of the link between mutant SOD1 and mitochondrial dysfunctions remains to be established. Here, we briefly review the evidence for mitochondrial dysfunctions in familial ALS and discuss a possible link between mutant SOD1 and mitochondrial dysfunction.",
    	author = "Faes, Liesbeth and Callewaert, Geert",
    	doi = "10.1007/s10863-011-9393-0",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Faes, Callewaert - 2011 - Mitochondrial dysfunction in familial amyotrophic lateral sclerosis.pdf:pdf",
    	issn = "1573-6881",
    	journal = "Journal of bioenergetics and biomembranes",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: enzymology,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: pathology,Animals,Genetic Diseases, Inborn,Genetic Diseases, Inborn: enzymology,Genetic Diseases, Inborn: genetics,Genetic Diseases, Inborn: pathology,Humans,Mitochondria,Mitochondria: enzymology,Mitochondria: genetics,Mitochondria: pathology,Mutation,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism",
    	month = "",
    	number = 6,
    	pages = "587--92",
    	pmid = 22072073,
    	title = "{Mitochondrial dysfunction in familial amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22072073",
    	volume = 43,
    	year = 2011
    }
    
  10. Ralf J Braun, Cornelia Sommer, Didac Carmona-Gutierrez, Chamel M Khoury, Julia Ring, Sabrina Büttner and Frank Madeo.
    Neurotoxic 43-kDa TAR DNA-binding protein (TDP-43) triggers mitochondrion-dependent programmed cell death in yeast.. The Journal of biological chemistry 286(22):19958–72, 2011.
    Abstract Pathological neuronal inclusions of the 43-kDa TAR DNA-binding protein (TDP-43) are implicated in dementia and motor neuron disorders; however, the molecular mechanisms of the underlying cell loss remain poorly understood. Here we used a yeast model to elucidate cell death mechanisms upon expression of human TDP-43. TDP-43-expressing cells displayed markedly increased markers of oxidative stress, apoptosis, and necrosis. Cytotoxicity was dose- and age-dependent and was potentiated upon expression of disease-associated variants. TDP-43 was localized in perimitochondrial aggregate-like foci, which correlated with cytotoxicity. Although the deleterious effects of TDP-43 were significantly decreased in cells lacking functional mitochondria, cell death depended neither on the mitochondrial cell death proteins apoptosis-inducing factor, endonuclease G, and cytochrome c nor on the activity of cell death proteases like the yeast caspase 1. In contrast, impairment of the respiratory chain attenuated the lethality upon TDP-43 expression with a stringent correlation between cytotoxicity and the degree of respiratory capacity or mitochondrial DNA stability. Consistently, an increase in the respiratory capacity of yeast resulted in enhanced TDP-43-triggered cytotoxicity, oxidative stress, and cell death markers. These data demonstrate that mitochondria and oxidative stress are important to TDP-43-triggered cell death in yeast and may suggest a similar role in human TDP-43 pathologies.
    URL, DOI BibTeX

    @article{Braun2011,
    	abstract = "Pathological neuronal inclusions of the 43-kDa TAR DNA-binding protein (TDP-43) are implicated in dementia and motor neuron disorders; however, the molecular mechanisms of the underlying cell loss remain poorly understood. Here we used a yeast model to elucidate cell death mechanisms upon expression of human TDP-43. TDP-43-expressing cells displayed markedly increased markers of oxidative stress, apoptosis, and necrosis. Cytotoxicity was dose- and age-dependent and was potentiated upon expression of disease-associated variants. TDP-43 was localized in perimitochondrial aggregate-like foci, which correlated with cytotoxicity. Although the deleterious effects of TDP-43 were significantly decreased in cells lacking functional mitochondria, cell death depended neither on the mitochondrial cell death proteins apoptosis-inducing factor, endonuclease G, and cytochrome c nor on the activity of cell death proteases like the yeast caspase 1. In contrast, impairment of the respiratory chain attenuated the lethality upon TDP-43 expression with a stringent correlation between cytotoxicity and the degree of respiratory capacity or mitochondrial DNA stability. Consistently, an increase in the respiratory capacity of yeast resulted in enhanced TDP-43-triggered cytotoxicity, oxidative stress, and cell death markers. These data demonstrate that mitochondria and oxidative stress are important to TDP-43-triggered cell death in yeast and may suggest a similar role in human TDP-43 pathologies.",
    	author = {Braun, Ralf J and Sommer, Cornelia and Carmona-Gutierrez, Didac and Khoury, Chamel M and Ring, Julia and B\"{u}ttner, Sabrina and Madeo, Frank},
    	doi = "10.1074/jbc.M110.194852",
    	issn = "1083-351X",
    	journal = "The Journal of biological chemistry",
    	keywords = "Cell Death,Cell Death: genetics,DNA, Fungal,DNA, Fungal: genetics,DNA, Fungal: metabolism,DNA, Mitochondrial,DNA, Mitochondrial: genetics,DNA, Mitochondrial: metabolism,DNA-Binding Proteins,DNA-Binding Proteins: biosynthesis,DNA-Binding Proteins: genetics,Humans,Mitochondria,Mitochondria: genetics,Mitochondria: metabolism,Oxidative Stress,Oxygen Consumption,Oxygen Consumption: genetics,Recombinant Proteins,Recombinant Proteins: biosynthesis,Recombinant Proteins: genetics,Saccharomyces cerevisiae,Saccharomyces cerevisiae: genetics,Saccharomyces cerevisiae: metabolism,TDP-43 Proteinopathies,TDP-43 Proteinopathies: genetics,TDP-43 Proteinopathies: metabolism,TDP-43 Proteinopathies: pathology",
    	month = "",
    	number = 22,
    	pages = "19958--72",
    	pmid = 21471218,
    	title = "{Neurotoxic 43-kDa TAR DNA-binding protein (TDP-43) triggers mitochondrion-dependent programmed cell death in yeast.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3103370\&tool=pmcentrez\&rendertype=abstract",
    	volume = 286,
    	year = 2011
    }
    
  11. Adrian Israelson, Nir Arbel, Sandrine Da Cruz, Hristelina Ilieva, Koji Yamanaka, Varda Shoshan-Barmatz and Don W Cleveland.
    Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS.. Neuron 67(4):575–87, August 2010.
    Abstract Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons. With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane. This interaction is found on isolated spinal cord mitochondria and can be reconstituted with purified components in vitro. ADP passage through the outer membrane is diminished in spinal mitochondria from mutant SOD1-expressing ALS rats. Direct binding of mutant SOD1 to VDAC1 inhibits conductance of individual channels when reconstituted in a lipid bilayer. Reduction of VDAC1 activity with targeted gene disruption is shown to diminish survival by accelerating onset of fatal paralysis in mice expressing the ALS-causing mutation SOD1(G37R). Taken together, our results establish a direct link between misfolded mutant SOD1 and mitochondrial dysfunction in this form of inherited ALS.
    URL, DOI BibTeX

    @article{Israelson2010,
    	abstract = "Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons. With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane. This interaction is found on isolated spinal cord mitochondria and can be reconstituted with purified components in vitro. ADP passage through the outer membrane is diminished in spinal mitochondria from mutant SOD1-expressing ALS rats. Direct binding of mutant SOD1 to VDAC1 inhibits conductance of individual channels when reconstituted in a lipid bilayer. Reduction of VDAC1 activity with targeted gene disruption is shown to diminish survival by accelerating onset of fatal paralysis in mice expressing the ALS-causing mutation SOD1(G37R). Taken together, our results establish a direct link between misfolded mutant SOD1 and mitochondrial dysfunction in this form of inherited ALS.",
    	author = "Israelson, Adrian and Arbel, Nir and {Da Cruz}, Sandrine and Ilieva, Hristelina and Yamanaka, Koji and Shoshan-Barmatz, Varda and Cleveland, Don W",
    	doi = "10.1016/j.neuron.2010.07.019",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Israelson et al. - 2010 - Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS.pdf:pdf",
    	issn = "1097-4199",
    	journal = "Neuron",
    	keywords = "Adenosine Diphosphate,Adenosine Diphosphate: metabolism,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: mortality,Animals,Calcium,Calcium: metabolism,Disease Models, Animal,Electric Conductivity,Humans,Lipid Bilayers,Lipid Bilayers: chemistry,Lipid Bilayers: metabolism,Mice,Mice, Transgenic,Mitochondria,Mitochondria: chemistry,Mitochondria: metabolism,Mitochondrial Membranes,Mitochondrial Membranes: chemistry,Mitochondrial Membranes: metabolism,Mutation, Missense,Paralysis,Paralysis: metabolism,Paralysis: mortality,Protein Folding,Rats,Rats, Transgenic,Spinal Cord,Spinal Cord: chemistry,Spinal Cord: metabolism,Superoxide Dismutase,Superoxide Dismutase: chemistry,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism,Voltage-Dependent Anion Channel 1,Voltage-Dependent Anion Channel 1: chemistry,Voltage-Dependent Anion Channel 1: genetics,Voltage-Dependent Anion Channel 1: metabolism",
    	month = "aug",
    	number = 4,
    	pages = "575--87",
    	pmid = 20797535,
    	title = "{Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2941987\&tool=pmcentrez\&rendertype=abstract",
    	volume = 67,
    	year = 2010
    }
    
  12. Ya-Fei Xu, Tania F Gendron, Yong-Jie Zhang, Wen-Lang Lin, Simon D'Alton, Hong Sheng, Monica Castanedes Casey, Jimei Tong, Joshua Knight, Xin Yu, Rosa Rademakers, Kevin Boylan, Mike Hutton, Eileen McGowan, Dennis W Dickson, Jada Lewis and Leonard Petrucelli.
    Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice.. The Journal of neuroscience : the official journal of the Society for Neuroscience 30(32):10851–9, 2010.
    Abstract Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.
    URL, DOI BibTeX

    @article{Xu2010,
    	abstract = "Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.",
    	author = "Xu, Ya-Fei and Gendron, Tania F and Zhang, Yong-Jie and Lin, Wen-Lang and D'Alton, Simon and Sheng, Hong and Casey, Monica Castanedes and Tong, Jimei and Knight, Joshua and Yu, Xin and Rademakers, Rosa and Boylan, Kevin and Hutton, Mike and McGowan, Eileen and Dickson, Dennis W and Lewis, Jada and Petrucelli, Leonard",
    	doi = "10.1523/JNEUROSCI.1630-10.2010",
    	issn = "1529-2401",
    	journal = "The Journal of neuroscience : the official journal of the Society for Neuroscience",
    	keywords = "Analysis of Variance,Animals,Body Weight,Body Weight: genetics,Brain,Brain: metabolism,Brain: pathology,Brain: ultrastructure,DNA-Binding Proteins,DNA-Binding Proteins: genetics,DNA-Binding Proteins: metabolism,GTP Phosphohydrolases,GTP Phosphohydrolases: metabolism,Gene Expression Regulation,Gene Expression Regulation: genetics,Humans,Mice,Mice, Transgenic,Microscopy, Electron, Transmission,Microscopy, Electron, Transmission: methods,Microtubule-Associated Proteins,Microtubule-Associated Proteins: metabolism,Mitochondria,Mitochondria: genetics,Mitochondria: metabolism,Mitochondria: pathology,Mitochondrial Proteins,Mitochondrial Proteins: metabolism,Motor Neurons,Motor Neurons: metabolism,Motor Neurons: pathology,Motor Neurons: ultrastructure,Movement Disorders,Movement Disorders: genetics,Movement Disorders: metabolism,Movement Disorders: mortality,Mutation,Mutation: genetics,Nerve Degeneration,Nerve Degeneration: genetics,Nerve Degeneration: mortality,Nerve Degeneration: pathology,Phosphorylation,Phosphorylation: genetics,Prions,Prions: genetics,Prions: metabolism,Silver Staining,Silver Staining: methods,Spinal Cord,Spinal Cord: metabolism,Spinal Cord: pathology,Spinal Cord: ultrastructure",
    	month = "",
    	number = 32,
    	pages = "10851--9",
    	pmid = 20702714,
    	title = "{Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3056148\&tool=pmcentrez\&rendertype=abstract",
    	volume = 30,
    	year = 2010
    }
    
  13. Andoni Echaniz-Laguna, Joffrey Zoll, Elodie Ponsot, Benoit N'guessan, Christine Tranchant, Jean-Philippe Loeffler and Eliane Lampert.
    Muscular mitochondrial function in amyotrophic lateral sclerosis is progressively altered as the disease develops: a temporal study in man.. Experimental neurology 198(1):25–30, 2006.
    Abstract We performed repeated analysis of mitochondrial respiratory function in skeletal muscle (SM) of patients with early-stage sporadic amyotrophic lateral sclerosis (SALS) to determine whether mitochondrial function was altered as the disease advanced. SM biopsies were obtained from 7 patients with newly diagnosed SALS, the same 7 patients 3 months later, and 7 sedentary controls. Muscle fibers were permeabilized with saponin, then skinned and placed in an oxygraphic chamber to measure basal and maximal adenosine diphosphate (ADP)-stimulated respiration rates and to assess mitochondrial regulation by ADP. We found that the maximal oxidative phosphorylation capacity of muscular mitochondria significantly increased, and muscular mitochondrial respiratory complex IV activity significantly decreased as the disease advanced. This temporal study demonstrates for the first time that mitochondrial function in SM in human SALS is progressively altered as the disease develops.
    URL, DOI BibTeX

    @article{Echaniz-Laguna2006,
    	abstract = "We performed repeated analysis of mitochondrial respiratory function in skeletal muscle (SM) of patients with early-stage sporadic amyotrophic lateral sclerosis (SALS) to determine whether mitochondrial function was altered as the disease advanced. SM biopsies were obtained from 7 patients with newly diagnosed SALS, the same 7 patients 3 months later, and 7 sedentary controls. Muscle fibers were permeabilized with saponin, then skinned and placed in an oxygraphic chamber to measure basal and maximal adenosine diphosphate (ADP)-stimulated respiration rates and to assess mitochondrial regulation by ADP. We found that the maximal oxidative phosphorylation capacity of muscular mitochondria significantly increased, and muscular mitochondrial respiratory complex IV activity significantly decreased as the disease advanced. This temporal study demonstrates for the first time that mitochondrial function in SM in human SALS is progressively altered as the disease develops.",
    	author = "Echaniz-Laguna, Andoni and Zoll, Joffrey and Ponsot, Elodie and N'guessan, Benoit and Tranchant, Christine and Loeffler, Jean-Philippe and Lampert, Eliane",
    	doi = "10.1016/j.expneurol.2005.07.020",
    	issn = "0014-4886",
    	journal = "Experimental neurology",
    	keywords = "Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: physiopathology,Case-Control Studies,Cell Membrane Permeability,Cell Membrane Permeability: drug effects,Cell Membrane Permeability: physiology,Disease Progression,Electromyography,Electromyography: methods,Exercise Test,Exercise Test: methods,Female,Follow-Up Studies,Humans,Male,Middle Aged,Mitochondria, Muscle,Mitochondria, Muscle: pathology,Multienzyme Complexes,Multienzyme Complexes: metabolism,Muscle Fibers, Skeletal,Muscle Fibers, Skeletal: drug effects,Muscle Fibers, Skeletal: metabolism,Muscle, Skeletal,Muscle, Skeletal: cytology,Muscle, Skeletal: metabolism,Muscle, Skeletal: physiopathology",
    	month = "",
    	number = 1,
    	pages = "25--30",
    	pmid = 16126198,
    	title = "{Muscular mitochondrial function in amyotrophic lateral sclerosis is progressively altered as the disease develops: a temporal study in man.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/16126198",
    	volume = 198,
    	year = 2006
    }
    

 

 

Mitochondria Pathology in Amyotrophic Lateral Sclerosis and Huntington’s Disease 

Neurodegeneration: Opportunities for Collaboration Across Disease-Specific Research and 

Development Communities - A Workshop : Session 3 

April 30, 2012 

Neil W. Kowall, M.D. 

VA Boston Healthcare System 

Boston University School of Medicine

http://www.iom.edu/~/media/Files/Activity%20Files/Research/NeuroForum/2012-APR-30/Presentations/310%20IOM%20presentation%20April%2030v6%20Kowall.pdf