Table 1.
Reported mitochondrial abnormalities in ALS. The types of mitochondrial changes and the model system or patient's tissue, in which they were found, are indicated. The findings listed at the bottom of the table refer to mitochondrial changes induced by mutant SOD1 specifically targeted to mitochondria. NO, nitric oxide; ETC, electron transfer chain; lysRS, lysyl-tRNA sythetase; UCP3, uncoupling protein 3.
| Mitochondrial abnormalities | Tissue and disease model | References |
|---|---|---|
| Swollen and vacuolated mitochondria | MN of mutant SOD1 mice | Dal Canto and Gurney, 1994; Kong and Xu, 1998; Higgins et al., 2002; Higgins et al., 2003; Sasaki et al., 2005; Doi et al., 2008 |
| Aggregated and swollen mitochondria | Post-mortem sporadic ALS spinal cord | Sasaki and Iwata, 1996; Sasaki and Iwata, 2007 |
| Swollen and fragmented mitochondria | N2A and NSC34 cells | Menzies et al., 2002; Magrane et al., 2009 |
| Decreased oxygen consumption | Brain, spinal cord, G93A SOD1 mice | Jung et al., 2002; Kirkinezos et al., 2005; Mattiazzi et al., 2002 |
| Decreased ATP synthesis | Brain, spinal cord, G93A SOD1 mice | Mattiazzi et al., 2002 |
| Reduced ETC activity, respiration, mitochondrial redox state alteration | NSC34 cells | Ferri et al., 2006 |
| Reduced ETC activity, respiration, ROS production | Mutant G93A mice, primary astrocytes | Cassina et al., 2008 |
| Reduced ETC activity, complex IV | Brain, spinal cord, G93A SOD1 mice, G93A×CCS mice | Jung et al., 2002; Mattiazzi et al., 2002; Kirkinezos et al., 2005; Son et al., 2007 |
| Complex IV assembly defect | G93A×CCS mice | Son et al., 2008 |
| Decreased complex II, complex IV activities | NSC34 cells | Menzies et al., 2002 |
| Decreased complex IV activity involving NO | NSC34 cells | Arciello et al., 2009 |
| Apoptosis activation | Mutant SOD1 mice, N2A cells | Pasinelli et al., 2000; Guegan et al., 2002; Wootz et al., 2004; Oh et al., 2006 |
| Mitochondrial axonal transport defect | Mutant G93A mice, primary motor neurons | De Vos et al., 2007 |
| Mislocalization of mitochondria | Mutant G93A mice, motor axons | Sotelo-Silveira et al., 2009 |
| Mutant SOD1 aggregation in mitochondria | Mutant SOD1 mice, brain, spinal cord | Higgins et al., 2001; Jaarsma et al., 2001; Okado-Matsumoto and Fridovich, 2001; Mattiazzi et al., 2002; Higgins et al., 2002; Liu et al., 2004; Pasinelli et al., 2004; Vijayvergiya et al., 2005; Deng et al., 2006; Vande Velde et al., 2008 |
| Mutant SOD1 aggregation in mitochondria | NSC 34 cells | Ferri et al., 2006; Cozzolino et al., 2009 |
| Mitochondrial protein import of lysRS | COS cells | Kawamata et al., 2008 |
| Calcium uptake defect | G93A and G85R mice, brain, spinal cord | Damiano et al., 2006 |
| Prolonged calcium-induced membrane potential depolarization | Mutant SOD1 mice, motor nerve terminals | Nguyen et al., 2009 |
| Calcium uptake defect | G93A mice, brainstem slice | Jaiswal and Keller, 2009 |
| Impaired calcium stores in mitochondria | SH-SY5Y cells | Jaiswal et al., 2009 |
| Mitochondrial calcium handling defect | G93A mice, muscle | Zhou et al., 2009 |
| Decreased respiratory chain activity | ALS patients, skeletal muscle | Wiedemann et al., 1998; Vielhaber et al., 1999; Vielhaber et al., 2000 |
| UCP3 upregulation | ALS patients, G93A mice, muscle | Dupuis et al., 2003 |
| Oxidative damage, SOD1 enzyme upregulation | Mutant SOD1 mice, skeletal muscle | Mahoney et al., 2006 |
| Mitochondrial morphological abnormalities | Mutant SOD1 mice with muscle specific SOD1 expression | Dobrowolny et al., 2008 |
| Mitochondrial abnormalities | System & SOD1 targeted to mitochondria | References |
| Induction of apoptosis | N2A cells, SOD1 targeted to matrix | Takeuchi et al., 2002 |
| Axonal transport defect, mitochondrial depolarization | NSC34 cells, SOD1 targeted to IMS | Magrane et al., 2009 |
| Abnormal morphology, caspase-3 activation | NSC34 cells, SOD1 targeted to IMS | Cozzolino et al., 2009 |