Decreased cytochrome c oxidase activity but unchanged superoxide dismutase and glutathione peroxidase activities in the spinal cords of patients with amyotrophic lateral sclerosis

Fujita, Kazuo; Yamauchi, Masamitsu; Shibayama, Keigo; Ando, Masahiko; Honda, Masao; Nagata, Yutaka

doi:10.1002/(sici)1097-4547(19960801)45:3<276::aid-jnr9>3.0.co;2-a

Cited by 121 publications

(53 citation statements)

References 24 publications

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“…In addition, high power microscopy evidenced damage to cristae, edema and altered membrane continuity. These findings are in consonance with mitochondrial abnormalities reported in the central nervous system of SALS patients and animal models of motor neuron degeneration 8,10 . Our present investigation suggests that changes taking place in skin mitochondria may reflect to some extent the mitochondrial abnormalities of the degenerating nervous system.…”

Section: Discussionsupporting

confidence: 89%

“…Afifi and colleagues 6 first reported abnormal mitochondrial morphology in the atrophic muscles of SALS patients and, subsequently, mitochondrial abnormalities have been reported in the central nervous system [7][8][9][10] , liver cells 11 and peripheral blood lymphocytes 12 of SALS patients. Muscle biopsies in SALS have shown increased mitochondrial volume associated to increased calcium levels 13 ; also, reduced activity of mitochondrial respiratory chain complex I and complex IV in skeletal muscle and the spinal cord have been reported 14,15 .…”

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confidence: 99%

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Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis

Rodríguez

González

Monachelli

et al. 2012

Arq. Neuro-Psiquiatr.

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OBJECTIVES: Mitochondrial dysfunction has been reported in the central nervous system, hepatocytes and peripheral blood lymphocytes from patients with sporadic amyotrophic lateral sclerosis (SALS). However, the status of skin mitochondria has not been reported, in spite of the fact that SALS patients present skin abnormalities. The objective of the present study was to compare mitochondrial ultrastructural parameters in keratinocytes from patients with SALS and healthy controls. METHODS: Our study was based on the analysis of 112 skin mitochondria from 5 SALS patients and 99 organelles from 4 control subjects by electron microscopy. RESULTS: Computerized image analysis showed that mitochondrial major axis length, area and perimeter of the organelle were significantly smaller in SALS respect of healthy control subjects. Morphologically, SALS mitochondria presented cristolysis and breakage of the outer membrane. CONCLUSIONS: Mitochondrial dysfunction in the skin may possibly reflect changes occurring in mitochondria of the central nervous system. The analysis of mitochondrial morphology in this tissue may be of value to follow disease progression and, eventually, the effectiveness of current therapies for SALS.

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis

Rodríguez

González

Monachelli

et al. 2012

Arq. Neuro-Psiquiatr.

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“…Similarly, a decrease in complex I activity was detected in muscle biopsy from sporadic ALS patients (Wiedemann et al 1998;Vielhaber et al 2000). Furthermore, a decrease in complex IV activity was detected in spinal cords of patients that had died of ALS (Fujita et al 1996;Borthwick et al 1999). In cultured neuroblastoma cells transfected with G93A mutant SOD1, Carri et al (1997) observed a decrease in mitochondrial membrane potential.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis

Jung

Higgins

2002

Journal of Neurochemistry

183

111

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Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that causes degeneration of motoneurons. Mutation of Cu,Zn superoxide dismutase (SOD1) is one cause for this disease. In mice, expression of mutant protein causes motoneuron degeneration and paralysis resembling the human disease. Morphological change, indicative of mitochondrial damage, occurs at early stages of the disease. To determine whether mitochondrial function changes during the course of disease progression, enzyme activities of mitochondrial electron transport chain in spinal cords from mice at different disease stages were measured using three different methods: spectrophotometric assay, in situ histochemical enzyme assay, and blue native gel electrophoresis combined with in-gel histochemical reaction. The enzyme activities were decreased in the spinal cord, particularly in the ventral horn, beginning at early disease stages. This decrease persisted throughout the course of disease progression. This decrease was not detected in the spinal cords of non-transgenic animals, of mice expressing the wild-type protein, and in cerebellum and dorsal horn of the spinal cords from mice expressing mutant protein. These results demonstrate a functional defect in mitochondria in the ventral horn region and support the view that mitochondrial damage plays a role in mutant SOD1-induced motoneuron degeneration pathway.

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“…There is growing evidence suggesting that mitochondria may be involved in the pathogenesis of ALS. In studies of spinal cord from SALS patients, a decrease in activity of cytochrome c oxidase (COX) was observed (Fujita et al, 1996;Borthwick et al, 1999). SOD1 mutant transgenic models showed prominent structural mitochondrial abnormalities (Wong et al, 1995;Kong and Xu, 1998).…”

Section: Introductionmentioning

confidence: 99%

CytochromecAssociation with the Inner Mitochondrial Membrane Is Impaired in the CNS of G93A-SOD1 Mice

Kirkinezos¹,

et al. 2005

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A "gain-of-function" toxic property of mutant Cu-Zn superoxide dismutase 1 (SOD1) is involved in the pathogenesis of some familial cases of amyotrophic lateral sclerosis (ALS). Expression of a mutant form of the human SOD1 gene in mice causes a degeneration of motor neurons, leading to progressive muscle weakness and hindlimb paralysis. Transgenic mice overexpressing a mutant human SOD1 gene (G93A-SOD1) were used to examine the mitochondrial involvement in familial ALS. We observed a decrease in mitochondrial respiration in brain and spinal cord of the G93A-SOD1 mice. This decrease was significant only at the last step of the respiratory chain (complex IV), and it was not observed in transgenic wild-type SOD1 and nontransgenic mice. Interestingly, this decrease was evident even at a very early age in mice, long before any clinical symptoms arose. The effect seemed to be CNS specific, because no decrease was observed in liver mitochondria. Differences in complex IV respiration between brain mitochondria of G93A-SOD1 and control mice were abolished when reduced cytochrome c was used as an electron donor, pinpointing the defect to cytochrome c. Submitochondrial studies showed that cytochrome c in the brain of G93A-SOD1 mice had a reduced association with the inner mitochondrial membrane (IMM). Brain mitochondrial lipids, including cardiolipin, had increased peroxidation in G93A-SOD1 mice. These results suggest a mechanism by which mutant SOD1 can disrupt the association of cytochrome c with the IMM, thereby priming an apoptotic program.

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Decreased cytochrome c oxidase activity but unchanged superoxide dismutase and glutathione peroxidase activities in the spinal cords of patients with amyotrophic lateral sclerosis

Cited by 121 publications

References 24 publications

Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis

Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis

Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis

CytochromecAssociation with the Inner Mitochondrial Membrane Is Impaired in the CNS of G93A-SOD1 Mice

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