Brain, Vol. 123, No. 7, 1291-1292,
July 2000
© 2000 Oxford University Press
Editorial |
Mitochondria and the pathogenesis of ALS
Department of Neurology, Weill Medical College, and Department of Neurology, New York Presbyterian Hospital, Cornell University, New York, USA
Evidence implicating mitochondria as playing a crucial role in both necrotic and apoptotic cell death is rapidly accumulating. Mitochondria are essential in controlling specific apoptosis pathways (Green and Reed, 1998
). Mitochondrial calcium uptake is required for glutamate excitotoxicity and there is a correlation between increases in mitochondrial calcium and increases in free radical generation, which are linked with cell death (Stout et al., 1998). The mitochondrial permeability transition pore may be crucial in both necrotic and apoptotic cell death. Activation of the permeability transition pore increases the mitochondrial membrane permeability to solids with a molecular mass of up to 1.5 kDa (Bernardi, 1999). It is activated by increases in calcium, and free radicals and cyclosporin A inhibits its activation. Cyclosporin A blocks neuronal damage produced by hypoglycaemia and ischaemia in vivo (Friberg et al., 1998).
A potential role of mitochondria in amyotrophic lateral sclerosis (ALS) is gaining increasing support. In this issue of Brain, Vielhaber and colleagues report further evidence implicating mitochondrial dysfunction in ALS (Vielhaber et al., 2000). The authors examined muscle biopsies of patients with ALS, compared with normal controls and as compared with patients with spinal muscular atrophy. Using saponin permeable muscle fibres, they detected abnormalities in NADPH autofluorescence imaging. The authors' prior studies also showed abnormalities in complex I activity in the muscle biopsies of individuals with sporadic ALS compared with age-matched controls (Wiedemann et al., 1998). They also found that there were respiratory chain defects in individual fibres of 11 out of 17 patients with sporadic ALS. This correlated with the presence of cytochrome c oxidase negative muscle fibres on muscle histology. The authors quantified mitochondrial DNA by Southern blot and found diminished levels in 13 out of 17 patients and multiple deletions in one of the patients. Lastly, the authors found that there are decreased levels of membrane-associated mitochondrial manganese superoxide dismutase (SOD) in the ALS patients. Eight of the sporadic ALS patients had levels of the enzyme lower than the lowest value observed in the control group. It was suggested that the reduced levels of manganese SOD may contribute to mitochondrial damage and some of the observed mitochondrial abnormalities.
These findings are of considerable interest. They suggest that some sporadic ALS patients may have mitochondrial DNA damage that may contribute to disease pathogenesis. Nevertheless, the concern about the possibility that some of the alterations are related to dennervation persists, despite the control group of spinal muscular atrophy patients. Further studies will therefore be needed to determine whether these results are in fact definitive.
There is substantial other evidence implicating mitochondrial dysfunction in sporadic ALS. There are mitochondrial abnormalities in liver biopsies from individuals with sporadic ALS (Masui et al., 1985; Nakano et al., 1987). Muscle biopsies of individuals with sporadic ALS also show increased mitochondrial volume and calcium levels within the mitochondria (Siklos et al., 1996). Peripheral blood lymphocytes from individuals with sporadic ALS show increased cytosolic calcium and impaired responses to inhibitors of oxidative phosphorylation (Curti et al., 1996). A recent study showed that there was reduced cytochrome oxidase activity in anterior horn motor neurons of patients with sporadic ALS, while succinate dehydrogenase activity, which is encoded by the nuclear genome, showed normal activity (Borthwick et al., 1999).
There is also evidence for mitochondrial DNA abnormalities, which may contribute to observed changes in electron transport activities. An out-of-frame mutation of mitochondrial DNA encoded subunit I of cytochrome c oxidase was reported in an individual with otherwise typical motor neuron disease (Comi et al., 1998). An interesting technique for attempting to determine whether mitochondrial DNA plays a role in producing electron transport activity defects is to utilize cybrid cell lines. These are produced by fusing a patient's platelets into cell lines that are depleted of mitochondria. This then results in the mitochondria being present in a different nuclear context. If an electron transport defect is found, it implies that it is encoded on the mitochondrial genome. A study of ALS cybrids showed a significant decrease in complex I activity as well as trends toward reduced complex III and IV activities, and an increase in free radical scavenging enzyme activities (Swerdlow et al., 1998).
Another set of observations, suggesting that mitochondrial dysfunction may play a role in the pathogenesis of ALS are findings in transgenic mice which have point mutations in the enzyme copper–zinc SOD. These point mutations have been associated with autosomal dominant inherited familial ALS (Rosen et al., 1993). Neuropathological studies of transgenic mice with copper–zinc SOD mutations showed that mitochondrial vacuolization is an early pathological feature with at least two of the mutations (Dal Canto and Gurney, 1994; Wong et al., 1995). Mitochondrial vacuolization precedes a rapid phase of motor weakness and loss of motor neurones in mice with the G93A copper–zinc SOD1 mutation (Kong and Xu, 1998). Furthermore, treatment of these mice with creatine, which may compensate for a bioenergetic defect, significantly improves survival, motor performance and delays loss of anterior horn motor neurons (Klivenyi et al., 1999).
The present study provides further evidence implicating mitochondrial dysfunction in the pathogenesis of ALS. Either inherited or acquired mitochondrial DNA mutations could play a role. Definitive evidence for this will have to wait further genetic studies which will be difficult due to the sporadic inheritance of most cases of ALS. Nevertheless, if mitochondrial defects were found to play a role in disease pathogenesis, this would have broad ranging implications for therapy. Further studies will therefore be of considerable interest in attempting to understand the pathogenesis of cell death in ALS.
References
Bernardi P. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev 1999; 79: 1127–55.
Borthwick GM, Johnson MA, Ince PG, Shaw PJ, Turnbull DM. Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol 1999; 46: 787–90.[Web of Science][Medline]
Comi GP, Bordoni A, Salani S, Franceschina L, Sciacco M, Prelle A, et al. Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease. Ann Neurol 1998; 43: 110–16.[Web of Science][Medline]
Curti D, Malaspina A, Facchetti G, Camana C, Mazzini L, Tosca P, et al. Amyotrophic lateral sclerosis: oxidative energy metabolism and calcium homeostasis in peripheral blood lymphocytes. Neurology 1996; 47: 1060–4.
Dal Canto MC, Gurney ME. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol 1994; 145: 1271–9.[Abstract]
Friberg H, Ferrand-Drake M, Bengtsson F, Halestrap AP, Wieloch T. Cyclosporin A, but not FK 506, protects mitochondria and neurons against hypoglycemic damage and implicates the mitochondrial permeability transition in cell death. J Neurosci 1998; 18: 5151–9.
Green DR, Reed JC. Mitochondria and apoptosis. [Review]. Science 1998; 281: 1309–12.
Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, Andreassen OA, et al. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med 1999; 5: 347–50.[Web of Science][Medline]
Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci 1998; 18: 3241–50.
Masui Y, Mozai T, Kakehi K. Functional and morphometric study of the liver in motor neuron disease. J Neurol 1985; 232: 15–19.[Web of Science][Medline]
Nakano K, Hirayama K, Terao K. Hepatic ultrastructural changes and liver dysfunction in amyotrophic lateral sclerosis. Arch Neurol 1987; 44: 103–6.
Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familiar amyotrophic lateral sclerosis. Nature 1993; 362: 59–62.[Medline]
Siklos L, Engelhardt J, Harati Y, Smith RG, Joo F, Appel SH. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis. Ann Neurol 1996; 39: 203–19.[Web of Science][Medline]
Stout AK, Raphael HM, Kanterewicz BI, Klann E, Reynolds IJ. Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat Neurosci 1998; 1: 366–73.[Web of Science][Medline]
Swerdlow RH, Parks JK, Cassarino DS, Trimmer PA, Miller SW, Maguire DJ, et al. Mitochondria in sporadic amyotrophic lateral sclerosis. Exp Neurol 1998; 153: 135–42.[Web of Science][Medline]
Vielhaber S, Kunz D, Winkler K, Weidemann FR, Kirches E, Feistner H, et al. Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain 2000; 123: 1339–48.
Wiedemann FR, Winkler K, Kuznetsov AV, Bartels C, Vielhaber S, Feistner H, et al. Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis. J Neurol Sci 1998; 156: 65–72.[Web of Science][Medline]
Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, et al. An adverse property of a familiar ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 1995; 14: 1105–16.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. L. Ferrante, J. Shefner, H. Zhang, R. Betensky, M. O'Brien, H. Yu, M. Fantasia, J. Taft, M. F. Beal, B. Traynor, et al. Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS Neurology, December 13, 2005; 65(11): 1834 - 1836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P J Shaw Molecular and cellular pathways of neurodegeneration in motor neurone disease J. Neurol. Neurosurg. Psychiatry, August 1, 2005; 76(8): 1046 - 1057. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Bergmann and B. U. Keller Impact of mitochondrial inhibition on excitability and cytosolic Ca2+ levels in brainstem motoneurones from mouse J. Physiol., February 15, 2004; 555(1): 45 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Dangond, D. Hwang, S. Camelo, P. Pasinelli, M. P. Frosch, G. Stephanopoulos, G. Stephanopoulos, R. H. Brown Jr., and S. R. Gullans Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter Physiol Genomics, January 15, 2004; 16(2): 229 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Takeuchi, Y. Kobayashi, S. Ishigaki, M. Doyu, and G. Sobue Mitochondrial Localization of Mutant Superoxide Dismutase 1 Triggers Caspase-dependent Cell Death in a Cellular Model of Familial Amyotrophic Lateral Sclerosis J. Biol. Chem., December 20, 2002; 277(52): 50966 - 50972. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Cluskey and D B Ramsden Mechanisms of neurodegeneration in amyotrophic lateral sclerosis Mol. Pathol., December 1, 2001; 54(6): 386 - 392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Sturtz, K. Diekert, L. T. Jensen, R. Lill, and V. C. Culotta A Fraction of Yeast Cu,Zn-Superoxide Dismutase and Its Metallochaperone, CCS, Localize to the Intermembrane Space of Mitochondria. A PHYSIOLOGICAL ROLE FOR SOD1 IN GUARDING AGAINST MITOCHONDRIAL OXIDATIVE DAMAGE J. Biol. Chem., October 5, 2001; 276(41): 38084 - 38089. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||