Mutation in the NDUFS4 gene of complex I abolishes cAMP‐dependent activation of the complex in a child with fatal neurological syndrome

Papa, Sergio; Scacco, Salvatore; Sardanelli, Anna Maria; Vergari, Rosaria; Papa, Francesco; Budde, Sandy; Heuvel, Lambert van den; Smeitink, Jan A.M.

doi:10.1016/s0014-5793(00)02334-6

Cited by 89 publications

(53 citation statements)

References 19 publications

(28 reference statements)

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“…Fibroblast cultures from the three patients exhibited severe depression of the normal activity of complex I, which also did not respond to activation by cAMP as observed in control cells from normal subjects (18). All mutations were found to be associated with impairment of the assembly of a normal, functional complex in the inner mitochondrial membrane.…”

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confidence: 78%

Pathological Mutations of the Human NDUFS4 Gene of the 18-kDa (AQDQ) Subunit of Complex I Affect the Expression of the Protein and the Assembly and Function of the Complex

Scacco

Petruzzella

Budde³

et al. 2003

Journal of Biological Chemistry

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122

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Presented is a study of the impact on the structure and function of human complex I of three different homozygous mutations in the NDUFS4 gene coding for the 18-kDa subunit of respiratory complex I, inherited by autosomal recessive mode in three children affected by a fatal neurological Leigh-like syndrome. The mutations consisted, respectively, of a AAGTC duplication at position 466 -470 of the coding sequence, a single base deletion at position 289/290, and a G44A nonsense mutation in the first exon of the gene. All three mutations were found to be associated with a defect of the assembly of a functional complex in the inner mitochondrial membrane. In all the mutations, in addition to destruction of the carboxyl-terminal segment of the 18-kDa subunit, the amino-terminal segment of the protein was also missing. In the mutation that was expected to produce a truncated subunit, the disappearance of the protein was associated with an almost complete disappearance of the NDUFS4 transcript. These observations show the essential role of the NDUFS4 gene in the structure and function of complex I and give insight into the pathogenic mechanism of NDUFS4 gene mutations in a severe defect of complex I.

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mentioning

confidence: 78%

Pathological Mutations of the Human NDUFS4 Gene of the 18-kDa (AQDQ) Subunit of Complex I Affect the Expression of the Protein and the Assembly and Function of the Complex

Scacco

Petruzzella

Budde³

et al. 2003

Journal of Biological Chemistry

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122

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“…The cAMP effects can be directly associated with phosphorylation of complex I subunits [9,[20][21][22] and or PKA-mediated changes in the redox [23]/nitrosylation [24] state of complex I subunits.…”

Section: Serum-limitation-induced Ros Production Is Not Associatedmentioning

confidence: 99%

cAMP controls oxygen metabolism in mammalian cells

et al. 2006

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The impact of cAMP on ROS-balance in human and mammalian cell cultures was studied. cAMP reduced accumulation of ROS induced by serum-limitation, under conditions in which there was no significant change in the activity of scavenger systems. This effect was associated with cAMP-dependent activation of the NADH-ubiquinone oxidoreductase activity of complex I. In fibroblasts from a patient a genetic defect in the 75 kDa FeS-protein subunit of complex I resulted in inhibition of the activity of the complex and enhanced ROS production, which were reversed by cAMP. A missense genetic defect in the NDUFS4 subunit, putative substrate of PKA, suppressed, on the other hand, the activity of the complex and prevented ROS production.

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“…Regulation of nuclear and mitochondrial gene expression, and targeting and further processing of individual polypeptides are evidently involved in long-term control of the amount (potential catalytic activity) of properly assembled Complex I. Recent ndings suggest that cAMP-dependent phosphorylation of the 18-kDa, nuclearencoded Complex I subunit may regulate the activity of the enzyme in cAMP-responsive tissues (38). What are other than classical respiratory control, the regulatory mechanisms, which allow a rapid response of the respiratory chain to the rapidly uctuating energy demands under physiological conditions?…”

Section: Perspectivesmentioning

confidence: 99%

The Mitochondrial Complex I: Progress in Understanding of Catalytic Properties

Vinogradov¹,

Grivennikova²

2001

IUBMB Life

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SummaryAlthough the mitochondrial Complex I has been extensively studied for over 4 decades, its catalytic properties in mitochondria are poorly understood. This review summarizes the data on standard and nonstandard kinetic parameters of the enzyme. The slow interconversion between active and deactivated forms of the mammalian Complex I (A/D transition) is described. We discuss the potential relevance of this transition for the regulation of NADH oxidation by the respiratory chain under physiological and pathophysiological conditions. IUBMB Life, 52: 129-134, 2001

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Mutation in the NDUFS4 gene of complex I abolishes cAMP‐dependent activation of the complex in a child with fatal neurological syndrome

Cited by 89 publications

References 19 publications

Pathological Mutations of the Human NDUFS4 Gene of the 18-kDa (AQDQ) Subunit of Complex I Affect the Expression of the Protein and the Assembly and Function of the Complex

Pathological Mutations of the Human NDUFS4 Gene of the 18-kDa (AQDQ) Subunit of Complex I Affect the Expression of the Protein and the Assembly and Function of the Complex

cAMP controls oxygen metabolism in mammalian cells

The Mitochondrial Complex I: Progress in Understanding of Catalytic Properties

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