An Assembled Complex IV Maintains the Stability and Activity of Complex I in Mammalian Mitochondria

Abstract

In the mammalian mitochondrial electron transfer system, the majority of electrons enter at complex I, go through complexes III and IV, and are finally delivered to oxygen. Previously we generated several mouse cell lines with suppressed expression of the nuclearly encoded subunit 4 of complex IV. This led to a loss of assembly of complex IV and its defective function. Interestingly, we found that the level of assembled complex I and its activity were also significantly reduced, whereas levels and activity of complex III were normal or up-regulated. The structural and functional dependence of complex I on complex IV was verified using a human cell line carrying a nonsense mutation in the mitochondrially encoded complex IV subunit 1 gene. Our work documents that, although there is no direct electron transfer between them, an assembled complex IV helps to maintain complex I in mammalian cells.

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…This is highly relevant because RC complexes associate in higher order assemblies called supercomplexes or respirasomes (Schagger and Pfeiffer, 2000;Schagger and Pfeiffer 2001;Schagger, 2002;Bianchi et al, 2004;Schagger et al, 2004;Dudkina et al, 2005, Boekema andBraun, 2007;Acin-Perez et al, 2008;Dudkina et al, 2011), which have been suggested to offer structural and functional advantages to the system, such as the prevention of the destabilization and degradation of RC complexes, the enhancement of electron transport efficiency and substrate channeling, or the reduction of electron or proton leakages Koopman et al, 2010;Lenaz and Genova, 2010). As a consequence of their organization in the respirasomes, structural interdependences amongst the individual RC complexes exist (Acin-Perez et al, 2004;Schagger et al, 2004;D'Aurelio et al, 2006;Diaz et al, 2006;Li et al, 2007;Saddar et al, 2008;Soto et al, 2009;Vempati et al, 2009). This has major biological as well as biomedical implications, since structural alterations primarily affecting one given complex often induce pleiotropic deleterious effects of the other enzymes.…”

“…As a result, combined RC enzyme deficiencies can be attributed to the genetic defect of a single complex. Mitochondrial complex I is functionally associated to the supercomplexes, and complexes III and IV are known play an essential role in the stabilization of complex I within these structures (AcinPerez et al, 2004;Schagger et al, 2004;Diaz et al, 2006;Li et al, 2007). For this reason structural alterations that severely impair the biosynthesis of complexes III and IV may induce pleiotropic deleterious effects on the assembly and enzyme activity of complex I that will be probably translated into combined respiratory deficiencies of two or more RC complexes.…”

“…Accordingly, alterations in the assembly and enzyme activities of the RC complexes I and IV were demonstrated in rat choroid plexus epithelial cells treated with Aβ, and also in human choroid plexus cells from patients suffering AD (Vargas et al, 2010). The import blockage of complex IV constituents towards mitochondria could lead to an abnormal assembly of complex IV and the respirasome, which in turn would be responsible for the partial loss of complex I activity (Schagger et al, 2004;Li et al, 2007;Moreno-Lastres et al, 2012). APP can not only alter mitochondrial function by blocking the mitochondrial protein import system, but can also exert its deleterious effects inside the organelle.…”

Cells Lacking Rieske Iron-Sulfur Protein Have a Reactive Oxygen Species-Associated Decrease in Respiratory Complexes I and IV

“…Generally, CI appears to be the most labile complex of the electron transport chain. Cells with defects in CIII or CIV assembly have decreased levels of CI (1,17,20,43), whereas cells lacking cytochrome c showed defects in CIV and CI (64). Likewise, defects in CV have been associated with defects in CIII and CIV in both yeast and mammalian cells (55,59).…”

Complex I Function Is Defective in Complex IV-deficient Caenorhabditis elegans

“…In human cell lines, high COX I mutation levels can lead to destabilization of complex I (11). In addition, inhibition of COX IV expression caused impairment in complex I assembly in mouse cell lines (21).…”