Mitochondrial dysfunction is a central pathological feature in amyotrophic lateral sclerosis (ALS), with evidence spanning genetic, biochemical, and clinical studies. Both familial and sporadic ALS show mitochondrial abnormalities, suggesting a shared final pathway in disease pathogenesis.
- Reduced ATP production via impaired oxidative phosphorylation
- Loss of mitochondrial membrane potential
- Increased mitochondrial permeability transition
- Excessive reactive oxygen species (ROS) production
- Damage to mitochondrial DNA, lipids, and proteins
- Compromised antioxidant defenses
- Impaired mitochondrial calcium buffering
- Excitotoxicity amplification
- Activation of apoptotic pathways
- Impaired clearance of damaged mitochondria
- Accumulation of dysfunctional mitochondria
- Mutations in PINK1, PARKIN associated with ALS
- Mitochondrial targeting of mutant SOD1
- Direct toxicity to mitochondrial complexes
- Disrupted electron transport chain
- Affects mitochondrial dynamics
- Alters mitophagy pathways
- Produces toxic dipeptide repeats
- Mitochondrial localization of TDP-43
- Disrupted mitochondrial RNA metabolism
- Altered mitochondrial gene expression
| Approach |
Target |
Status |
| CoQ10 |
Electron transport |
Phase 2 trials |
| Mitochondrial antioxidants |
ROS |
Preclinical |
| Mitophagy modulators |
PINK1/Parkin |
Research |
| Metabolic enhancers |
ATP production |
Phase 1 |