There is increasing evidence linking
mitochondrial dysfunction to
neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in
mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for
neurodegenerative diseases. This is the case in
Alzheimer's disease, in which there is evidence that both
beta-amyloid and the
amyloid precursor
protein may directly interact with mitochondria, leading to increased
free radical production. In the case of
Huntington's disease (HD), recent evidence suggests that the coactivator PGC1alpha, a key regulator of mitochondrial biogenesis in respiration, is down-regulated in patients with HD and in several animal models of this
neurodegenerative disorder. In
Parkinson's disease, the autosomal recessive genes parkin, DJ1 and PINK1 are all linked to either oxidative stress or
mitochondrial dysfunction. In
amyotrophic lateral sclerosis, there is strong evidence that mutant
superoxide dismutase directly interacts with the outer mitochondrial membrane as well as the intermembrane space and matrix. Therefore, an impressive number of disease specific
proteins interact with mitochondria.
Therapies that target basic mitochondrial processes such as energy metabolism in
free radical generation, or specific interactions of disease-related
protein with mitochondria, hold great promise.