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Human Complex I Deficiency: Clinical Spectrum and Involvement of Oxygen Free Radicals in the Pathogenicity of the Defect

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Human Complex I Deficiency: Clinical Spectrum and Involvement of Oxygen Free Radicals in the Pathogenicity of the Defect Biochimica et Biophysica Acta 1364Ž. 1998 271±286 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Human Complex I deficiency: Clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect Brian H. Robinson ) Departments of Biochemistry and Paediatrics, The UniÕersity of Toronto, Toronto, Ontario, Canada The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Received 27 October 1997; revised 12 January 1998; accepted 13 January 1998 Human NADH-ubiquinione oxidoreductase defi- contain at least 41 distinct proteins, it is not known ciency can be present in a wide variety of biochemi- how many of them are involved directly in transport cal and symptomatic phenotypes. In fact, the ob- of electrons coupled to vectorial proton movements. served spectrum of severity varies from fatal infantile The proteins of Complex I are traditionally divided lactic acidosis to adult onset exercise intolerance or up into flavoproteinŽ. FP , iron protein Ž. IP and hy- optic neuropathy. Since most genetic diseases display drophobic proteinŽ. HP fractionswx 1,2 . Mitochondria a much more narrow set of indices, perhaps this wide of higher animals have seven mitochondrially en- variety of clinical presentation requires some expla- coded proteins in Complex I that are intricately asso- nation. Many of the problems that revolve around the ciated with the inner mitochondrial membrane and diagnosis of Complex I defects stem from the fact are part of the HP fractionwx 3 . Based on the elbow or that Complex I is a huge multienzyme complex of 41 boomerang shape of Complex I observed by electron separately encoded gene products derived from both microscopy for the Neurospora crassa complex, the nuclear and mitochondrial genomeswx 1,2 . This dual subfractionation profiles of mammalian Complex I coding system leads to a number of difficulties, and the homology to bacterial hydrogenase and dehy- misconceptions and pitfalls surrounding etiology and drogenase complexes, a possible arrangement of the diagnosis. In addition, a further complicating factor major subunits can be predictedŽ. Fig. 1wx 4±9 . The related to oxygen free radical generation seems to be passage of electrons goes through an FMN centre an important factor in the determination of pathology located in the 51 kDa protein, then through a 4Fe±4S in affected individuals. centre on the same protein, through a 2Fe±2S centre in the 24 kDa protein, a 4Fe±4S centre in the 75 kDa protein and then probably through iron±sulfur centres 1. Basic principlesÐthe biology of Complex I on the 20 kDa and 23 kDa subunitswx 9,10 . The final acceptor of the electrons is ubiquinone although there Though Complex IŽ NADH-ubiquinone oxido- is evidence that at least two quinone acceptance loci reductase. in mammalian mitochondria appears to exist with different sensitivity to quinone analogue inhibitorswx 11±13 . The reaction mechanism whereby ) electron transfer is coupled to vectorial proton Corresponding author. The Research Institute, The Hospital wx for Sick Children, 555 University Avenue, Rm a9107, Toronto, translocation is not clear 10 . There is evidence that Ontario M5G 1X8, Canada. Fax: q1-416-813-4931; E-mail: a high titre of semiquinone radical is produced within [email protected] Complex I and that this semiquinone is an integral 0005-2728r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S0005-2728Ž. 98 00033-4 272 B.H. RobinsonrBiochimica et Biophysica Acta 1364() 1998 271±286 Fig. 1. Complex I of the mitochondrial respiratory chain. The complex is depicted as an elbow shaped assembly with one arm facing into the matrix and the other arm being associated with inner mitochondrial membrane. The subunits considered to be involved in the transport of electrons are the 51 K flavoprotein containing a 4Fe±4S centre, with the 24 K, 75 K, 23 K and 20 K iron sulfur proteins. Two quinone reduction sites are postulated. The mtDNA-encoded subunits are all part of the membrane arm of the complex and some of them are possibly involved in proton pumping functions. part of the reaction mechanismwx 14,15 . In order to wx13,16 . The function of the remaining six mtDNA produce vectorial proton movement via the move- encoded subunits remains obscure, though there are ment of electrons it is probable that the FeS centres some important clues from the patients affected with associated with the membrane arm of the complex, mutations in the ND subunits. It has been demon- i.e., the two centres in the 23 kDa TYKY subunit, strated that patients with mutations in the ND1 gene catalyse a vectorial movement of protons coupled to have defective electron transport while patients with semiquinone oxidationrreductionwx 10 . This becomes ND4 defects have no such defect but are unable to important later in the consideration of free radical carry out ATP synthesis from NAD linked substrates production in patients with Complex I deficiency. in isolated mitochondriawx 17 . This implies that a coupling function such as proton translocation is impaired in ND4 mutations. Since ND2, ND4 and 2. The supernumery subunits ND5 possess a certain amount of homology, it is not unreasonable to propose that these three subunits are Only one of the mtDNA encoded subunits appears all involved in proton transport in some waywx 18 . to have a defined role. The ND1 subunit has been The ND6 subunit is probably also involved in elec- shown to be the binding site for both rotenone and tron transport events since mutations in this subunit for photoaffinity-labelled ubiquinone analogues, sug- affect electron flow in Complex Iwx 18,19 . gesting that this is the terminal acceptor for quinone Of the 34 nuclear encoded subunits in the bovine reduction within the membrane portion of Complex I complex, the 75, 51, 49, 30, 24, 23 and 20 kDa B.H. RobinsonrBiochimica et Biophysica Acta 1364() 1998 271±286 273 subunits are equivalent to proteins present in bacterial Few functions have been assigned to the supernu- Complex Iwx 3 . There are another 27 proteins in the mery subunits not held in common with Paracoccus. mammalian complex as identified by Walker and The SDAP protein, a small 10 kDa protein with otherswx 20±33 . These proteins are unusual in that homology to acyl carrier proteins, appears to have a nine of them have blocked N-termini and no leader function in mitochondrial phospholipid metabolism sequence for import, while another nine proteins have wx40 and its removal in yeast and Neurospora seems no leader but an open N-terminus. Another nine have to impair a number of mitochondrial functions as the the more expected cleavable leader sequence desig- intramitochondrial lysophospholipid content is in- nating import into the matrix. The majority of the creased. The phosphorylation of at least four subunits leaderless peptides appear to be part of the hydropho- of Complex I have been described, namely the 42 bic membrane fractionŽ. Table 1 . kDa, 29 kDa, 18 kDa AQDQ subunit and the MWFE Table 1 Nuclear-encoded subunits of Complex I Name Mr Leader N-terminus Function Chromosome References 75 K FeS 75 q 4Fe±4S 2q33±34wx 21,22 51 K Fp 51 q Flavin, 4Fe±4S 11q13wx 25,34 49 K 49 qyChr 1wx 26,35 42 K 42 qyywx30 39 K 39 q Phosphorylation 12pwx 30 30 K 30 qyywx27 24 K FeS 24 q 2Fe±2S 18p11.3wx 27 23 K FeSŽ. TYKY 23 q 4Fe±4S 11q13wx 36 B22 22 y N-Acetyl y 8q13.3wx 37 PSST 20 q 3Fe±3S 19p13.2wx 29,38 PDSW 22 yy wx31 PGIV 19 yyywx28 ASH 1 18 q Phosphorylation? y wx33 SGDH 18 qyywx33 B18 18 y N-Myristoyl Phosphorylation? y wx33 18KIPŽ. AQDQ 18 q Phosphorylation? y wx33 B17 17 y N-Acetyl yywx33 B15 15 y N-Acetyl yywx33 B14.5aŽ. ASAT 14.5 y Q-binding 17wx 24 B14.5bŽ. MMTG 14.5 yyywx24 B14 14 y N-Acetyl yywx33 B13 13 y N-Acetyl yywx33 15 KŽ. 1P 15 yywx33 B12 12 y Unknown Mod yywx33 B8 8 y N-Acetyl yywx33 13 KŽ.Ž 1P DDGD . 13 qyywx33 MLRQ 9 yyywx33 B9 9 y Unknown Mod yywx33 AGGG 10 qyywx33 MWFE 6 y Phosphorylation Xq24wx 33,39 MNLL 5.5 yyywx33 KFY1 5 yyywx33 10 KŽ.Ž 1P SHES . 10 qyywx32 5DAP 10 y Acyl Carrier Protein y wx22 References are given for the subunit determined from Bostaurus, except for those with chromosomal allocations which have human cDNA clones reported. See text for details. 274 B.H. RobinsonrBiochimica et Biophysica Acta 1364() 1998 271±286 subunitwx 41 . Two of these proteins, namely the 18 eration, ventricular cardiomyopathy and spongy de- kDa AQDQ and the MWFE have been shown to be generation of the brain. Both had a chronically raised phosphorylated by cyclic AMP dependent kinase level of blood lactate with intermittent severe acido- wx41,42 . While there is some evidence that there is a sis. Two very well documented patients described by cyclic AMP dependent kinase activity which is mito- Fujii et al.wx 51 with Leigh disease had muscle Com- chondrial in location, it almost certainly resides on plex I deficiency. Both infants displayed damage to the outer membranewx 43 . It is not clear what phos- the putamen, thalamus and substantia nigra on CT phorylation does to the activity of Complex I. It scan of the brain. This agreed with data we reported seems that these subunits can be phosphorylated in an on 24 patients exhibiting Complex I deficiency, half atractyloside sensitive manner in whole mitochondria, of which had Leigh disease with possible associated but to what purpose is not clear at this timewx 44,45 .
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