The respiratory chain is a set of biochemically linked multisubunit complexes (complexes

I, II, III, and IV) and two electron carriers (ubiquinone/coenzyme Q and cytochrome c). It uses the energy stored in food to generate a proton gradient across the mitochondrial inner membrane, while at the same time transferring electrons to oxygen, producing water. The energy of the proton gradient this website drives ATP synthesis via ATP synthase (complex V); the ATP is then distributed throughout the cell. The central importance of mitochondria for cellular energy production is underscored by the discovery in the last 20 years of numerous syndromes resulting from OxPhos defects (DiMauro and Schon, 2003). The mitochondrial respiratory chain is the product of a joint effort between

the mitochondrial and nuclear genomes. Mitochondria harbor their own DNA (mtDNA) which is a 16.6 kb double-stranded circular DNA that encodes 13 of the ∼92 polypeptides of the OxPhos system (DiMauro and Schon, 2003), while the nuclear DNA (nDNA) specifies ∼79 OxPhos structural polypeptides and more than 100 other proteins required for the proper incorporation of cofactors (e.g., iron-sulfur proteins, hemes, and copper) and for the assembly of the 3-MA nmr five respiratory chain complexes into an integrated system (Fernández-Vizarra et al., 2009). Patients with OxPhos dysfunction who carry mutations in either mtDNA or nDNA present with a host of clinical features, many of which are neurological, such as seizures, myoclonus, ataxia, progressive muscle weakness, stroke-like episodes, and cognitive impairment (DiMauro and Schon, 2003). However, these manifestations do not typically overlap with either the clinical or the neuropathological hallmarks of any of our selected adult-onset neurodegenerative disorders (Table 1). Furthermore, to a remarkable degree, mutations in both mtDNA and nDNA that affect the integrity or functioning of the OxPhos complexes typically do not strike in adulthood, but rather in infancy (e.g., Leigh

syndrome, which is a fatal, necrotizing encephalopathy). Yet, some patients with OxPhos dysfunction do succumb later, in their twenties or thirties (e.g., via Kearns-Sayre syndrome, which is a sporadically occurring, fatal, multisystem disorder Idoxuridine featuring paralysis of the extraocular muscles, retinal degeneration, and heart block), but it is atypical for mitochondrial patients to survive much longer, and it is exceptional for any individual to experience an onset of an OxPhos disease beyond the age of 40. However, the age at onset and the severity of the disorder correlate well with the degree of ATP deficit caused by the mutation. Thus, “mild” mutations could theoretically give rise to a slowly progressive, late-onset neurodegenerative disease, such as AD or PD.