Abstract
Muscle diseases display mitochondrial dysfunction and oxidative damage. Our previous study in a cardiotoxin model of myodegeneration correlated muscle damage with mitochondrial dysfunction, which in turn entailed altered mitochondrial proteome and oxidative damage of mitochondrial proteins. Proteomic identification of oxidized proteins in muscle biopsies from muscular dystrophy patients and cardiotoxin model revealed specific mitochondrial proteins to be targeted for oxidation. These included respiratory complexes which displayed oxidative modification of Trp residues in different subunits. Among these, Ubiquinol-Cytochrome C Reductase Core protein 1 (UQCRC1), a subunit of Ubiquinol-Cytochrome C Reductase Complex or Cytochrome b-c1 Complex or Respiratory Complex III displayed oxidation of Trp395, which could be correlated with the lowered activity of Complex III. We hypothesized that Trp395 oxidation might contribute to altered local conformation and overall structure of Complex III, thereby potentially leading to altered protein activity. To address this, we performed molecular dynamics simulation of Complex III (oxidized at Trp395 of UQCRC1 vs. non-oxidized control). Molecular dynamic simulation analyses revealed local structural changes in the Trp395 site. Intriguingly, oxidized Trp395 contributed to decreased plasticity of Complex III due to significant cross-talk among the subunits in the matrix-facing region and subunits in the intermembrane space, thereby leading to impaired electron flow from cytochrome C.
Highlights
Muscle diseases display mitochondrial dysfunction and oxidative damage
Complex III (CIII) is composed of 11 subunits[8,9,10] that are arranged as a dimer, embedded in the inner mitochondrial membrane (Fig. 1A)
There exists crosstalk among the CIII subunits, which integrate transfer of electrons from ubiquinone to cytochrome C and proton pumping from the mitochondrial matrix into the inter-membrane space
Summary
Muscle diseases display mitochondrial dysfunction and oxidative damage. Our previous study in a cardiotoxin model of myodegeneration correlated muscle damage with mitochondrial dysfunction, which in turn entailed altered mitochondrial proteome and oxidative damage of mitochondrial proteins. Proteomic identification of oxidized proteins in muscle biopsies from muscular dystrophy patients and cardiotoxin model revealed specific mitochondrial proteins to be targeted for oxidation These included respiratory complexes which displayed oxidative modification of Trp residues in different subunits. Screening for Trp oxidation events in the MS data from the CTX model and muscle disease studies[2,3] revealed several mitochondrial proteins with oxidized Trp, including Aconitase, Voltage-dependent Anion Channels (VDAC), and subunits of mitochondrial complexes I, III and V among others, indicating that Trp oxidation might contribute to altered mitochondrial dynamics. Proteomics data in the CTX model[2] revealed that Ubiquinol-Cytochrome C Reductase Core protein 1 (UQCRC1; PDB Id: 1SQB), a subunit of Ubiquinol-Cytochrome C Reductase Complex or Cytochrome b-c1 Complex or mitochondrial Respiratory Complex III (CIII)[8] contained one oxidized Trp[395] (W395; +16 Da). In order to account for all the structural scenarios of CIII organization, we investigated oxidation-dependent structural changes in inhibitor-bound, substrate-bound, and unbound (apo-form) states of CIII
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