Significance of Respirasomes for the Assembly/Stability of Human Respiratory Chain Complex I

Abstract

We showed that the human respiratory chain is organized in supramolecular assemblies of respiratory chain complexes, the respirasomes. The mitochondrial complexes I (NADH dehydrogenase) and III (cytochrome c reductase) form a stable core respirasome to which complex IV (cytochrome c oxidase) can also bind. An analysis of the state of respirasomes in patients with an isolated deficiency of single complexes provided evidence that the formation of respirasomes is essential for the assembly/stability of complex I, the major entry point of respiratory chain substrates. Genetic alterations leading to a loss of complex III prevented respirasome formation and led to the secondary loss of complex I. Therefore, primary complex III assembly deficiencies presented as combined complex III/I defects. This dependence of complex I assembly/stability on respirasome formation has important implications for the diagnosis of mitochondrial respiratory chain disorders.

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Our studies revealed that while complexes III and IV can assemble either as individual holoenzymes or by incorporation of free subunits into supercomplexes, the respirasomes constitute the structural units where complex I is assembled and activated, thus explaining the essentiality of the respirasomes for complex I function (Schagger et al, 2004). Importantly, this model aids explaining the structural interdependences among OXPHOS complexes, and why certain genetic defects affecting a single complex may lead to combined RC enzyme defects in patients.…”

“…Such differences might be attributed to the nature of the mutation or the functional role of the OXPHOS mutated gene, and suggest that not all complexes III and IV structural genes are equally necessary to maintain complex I stability. The fact that complex III and complex IV can get assembled either as individual holoenzymes or by direct binding of free subunits to supercomplex assembly intermediates supports the existence of several independently-regulated assembly pathways for the biosynthesis of these two complexes, and explains why decreased complex I levels usually lead to isolated complex I deficiency in mammalian tissues (Acin-Perez et al, 2004;Schagger et al, 2004). However, once more exceptions have been reported (Budde et al, 2000;Ugalde et al, 2004;Saada et al, 2011), making necessary to gain more insight in the mechanisms that regulate the structural and functional interdependences between OXPHOS 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.…”

“…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.…”