Pathogenetic mechanisms in hereditary dysfunctions of complex I of the respiratory chain in neurological diseases.
This paper covers genetic and biochemical aspects of mitochondrial bioenergetics dysfunction in hereditary neurological disorders associated with complex I defects. Three types of hereditary complex I dysfunction are dealt with: (i) homozygous mutations in the nuclear genes NDUFS1 and NDUFS4 of complex I, associated with mitochondrial encephalopathy; (ii) a recessive hereditary epileptic neurological disorder associated with enhanced proteolytic degradation of complex I; (iii) homoplasmic mutations in the ND5 and ND6 mitochondrial genes of the complex, coexistent with mutation in the nuclear PINK1 gene in familial Parkinsonism. The genetic and biochemical data examined highlight different mechanisms by which mitochondrial bioenergetics is altered in these hereditary defects of complex I. This knowledge, besides clarifying molecular aspects of the pathogenesis of hereditary diseases, can also provide hints for understanding the involvement of complex I in sporadic neurological disorders and aging, as well as for developing therapeutical strategies.
Papa
Sergio
S
Department of Medical Biochemistry, Biology and Physics, University of Bari, Italy. papabchm@cimedoc.uniba.it
Petruzzella
Vittoria
V
Scacco
Salvatore
S
Sardanelli
Anna Maria
AM
Iuso
Arcangela
A
Panelli
Damiano
D
Vitale
Rita
R
Trentadue
Raffaella
R
De Rasmo
Domenico
D
Capitanio
Nazzareno
N
Piccoli
Claudia
C
Papa
Francesco
F
Scivetti
Michele
M
Bertini
Enrico
E
Rizza
Teresa
T
De Michele
Giuseppe
G
D000595:Amino Acid Sequence; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000737:chemistry / Q000235:genetics*; D004827:Epilepsy / Q000201:enzymology / Q000235:genetics; D006801:Humans; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics; D009422:Nervous System Diseases / Q000201:enzymology* / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
D004272:DNA, Mitochondrial; C487793:NDUFS1 protein, human; D017382:Reactive Oxygen Species; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C427643:NDUFS4 protein, human