Electron tunneling in respiratory complex I

Abstract

NADH:ubiquinone oxidoreductase (complex I) plays a central role in the respiratory electron transport chain by coupling the transfer of electrons from NADH to ubiquinone to the creation of the proton gradient across the membrane necessary for ATP synthesis. Here the atomistic details of electronic wiring of all Fe/S clusters in complex I are revealed by using the tunneling current theory and computer simulations; both density functional theory and semiempirical electronic structure methods were used to examine antiferromagnetically coupled spin states and corresponding tunneling wave functions. Distinct electron tunneling pathways between neighboring Fe/S clusters are identified; the pathways primarily consist of two cysteine ligands and one additional key residue. Internal water between protein subunits is identified as an essential mediator enhancing the overall electron transfer rate by almost three orders of magnitude to achieve a physiologically significant value. The identified key residues are further characterized by sensitivity of electron transfer rates to their mutations, examined in simulations, and their conservation among complex I homologues. The unusual electronic structure properties of Fe 4 S 4 clusters in complex I explain their remarkable efficiency of electron transfer.electron transfer in proteins | respiratory chain | iron-sulfur clusters N ADH:ubiquinone oxidoreductase (complex I) is a large L-shaped membrane-bound enzyme involved in cellular respiration that catalyzes the oxidation of NADH and the reduction of ubiquinone in mitochondria and respiring bacteria (1-3). This reaction involves the transfer of electrons over approximately 90 Å from NADH bound to the hydrophilic domain to ubiquinone in or near the hydrophobic membrane-bound domain of complex I (4). In turn, the reaction provides the driving force for translocation of four protons across the membrane, thus generating, in part, the proton gradient necessary for ATP synthesis (5). Complex I defects are the cause of several neurodegenerative diseases including Parkinson disease, Alzheimer's disease, and Huntington disease (6).The transfer of electrons from NADH to ubiquinone is facilitated by flavin mononucleotide (FMN), two binuclear (2Fe-2S) iron-sulfur clusters (N1a and N1b), and six tetranuclear (4Fe-4S) iron-sulfur clusters (N3, N4, N5, N6a, N6b, and N2) (Fig. 1A). NADH, a two-electron donor, initially passes both electrons, as hydride, to the FMN cofactor. From FMN one electron enters a transport chain leading to the ubiquinone-binding site; the second electron enters a side path to N1a that appears to serve as a control mechanism to prevent generation of superoxide ions (4).The crystal structure of hydrophilic domain of complex I from Thermus thermophilus was reported in 2006 (4), and recently the whole architecture of the enzyme has been revealed (7); however, until now, the atomistic details of electron transfer along the chain of Fe/S metal clusters have remained unknown. Recently, a hopping (stepwise) electron transfer (...

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

“…Mitochondrial ND2 and ND4 genes encode core subunits of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) (Mathiesen & Hagerhall, 2002; Brandt, 2006). Complex I functions in the transfer of electrons from NADH to the respiratory chain (Hayashi & Stuchebrukhov, 2010). Previous studies have shown that mRNA levels of mitochondrial genome‐encoded Complex I ( ND4 ), COX I, COX II, and COX III genes are significantly decreased in AD temporal cortex (Chandrasekaran et al ., 1996; Fukuyama et al ., 1996).…”

Electron Transfer in Subunit NuoI (TYKY) of Escherichia coli NADH:Quinone Oxidoreductase (NDH-1)

“…Individual electron tunneling paths were speculated to involve up to three residues, including two cysteine ligands and one additional key residue (37,60). A role of Ile-99 of the subunit Nqo9 of T. thermophilus NDH-1 (Ile100 in E. coli) was predicted for electron tunneling between N6b and N2.…”

“…Furthermore, it was hypothesized that the electron tunneling pathway in NDH-1 primarily consist of two cysteine ligands and one additional key residue (37). In the case of NuoI, the conserved Ile-100 and Ile-94 are predicted to play the role.…”

Randomly selected suppressor mutations in genes for NADH : quinone oxidoreductase-1, which rescue motility of a Salmonella ubiquinone-biosynthesis mutant strain

“…The role of the Cterminal domain of NuoG/Nqo3 in the function of NDH-1 is not fully understood. Residue E324 is located on the surface of Nqo3 and far from both the proposed electrontunneling pathway (Hayashi & Stuchebrukhov, 2010;…”