In mammalian cells, mitochondria provide energy from aerobic metabolism. They play an important regulatory role in apoptosis, produce and detoxify
free radicals, and serve as a cellular
calcium buffer.
Neurodegenerative disorders involving mitochondria can be divided into those caused by oxidative phosphorylation (OXPHOS) abnormalities either due to
mitochondrial DNA (
mtDNA) abnormalities, e.g., chronic
external ophthalmoplegia, or due to nuclear mutations of OXPHOS
proteins, e.g., complex I and II associated with
Leigh syndrome. There are diseases caused by nuclear genes encoding non-OXPHOS
mitochondrial proteins, such as
frataxin in
Friedreich ataxia (which is likely to play an important role in mitochondrial-cytosolic
iron cycling), paraplegin (possibly a mitochondrial
ATP-dependent
zinc metalloprotease of the
AAA-ATPases in hereditary
spastic paraparesis), and possibly
Wilson disease protein (an abnormal
copper transporting
ATP-dependent
P-type ATPase associated with
Wilson disease). Huntingon disease is an example of diseases with OXPHOS defects associated with mutations of nuclear genes encoding non-
mitochondrial proteins such as huntingtin. There are also disorders with evidence of mitochondrial involvement that cannot as yet be assigned. These include
Parkinson disease (where a complex I defect is described and
free radicals are generated from
dopamine metabolism),
amyotrophic lateral sclerosis, and
Alzheimer disease, where there is evidence to suggest mitochondrial involvement perhaps secondary to other abnormalities.