Mechanisms of mutant SOD1 induced mitochondrial toxicity in amyotrophic lateral sclerosis

Abstract

In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction is recognized as one of the key elements contributing to the pathology. Mitochondria are the major source of intracellular reactive oxygen species (ROS). Increased production of ROS as well as oxidative damage of proteins and lipids have been demonstrated in many models of ALS. Moreover, these changes were also observed in tissues of ALS patients indicative of important role for oxidative stress in the disease pathology. However, the origin of oxidative stress in ALS has remained unclear. ALS linked mutant Cu/Zn-superoxide dismutase 1 (SOD1) has been shown to significantly associate with mitochondria, especially in the spinal cord. In animal models, increased recruitment of mutant SOD1 (mutSOD1) to mitochondria appears already before the disease onset, suggestive of causative role for the manifestation of pathology. Recently, substantial in vitro and in vivo evidence has accumulated demonstrating that localization of mutSOD1 to the mitochondrial intermembrane space (IMS) inevitably leads to impairment of mitochondrial functions. However, the exact mechanisms of the selectivity and toxicity have remained obscure. Here we discuss the current knowledge on the role of mutSOD1 in mitochondrial dysfunction in ALS from the novel perspective emphasizing the misregulation of dismutase activity in IMS as a major mechanism for the toxicity.

Keywords: intermembrane space; misfolding; mitochondria; oxidative stress; superoxide dismutase activity.

Figure 1

Import of SOD1 and CCS into mitochondrial IMS. Unfolded apoforms of SOD1 and CCS are imported into the IMS of mitochondria through the translocator of the outer membrane (TOM) (reaction I). In the IMS, apoCCS interacts with the import receptor, Mia40. Upon this interaction an intramolecular disulfide bond is formed within CCS trapping it in IMS (reaction IIa). The translocation of mutant SOD1 (muSOD1) may take place via alternative mechanism involving the mitochondrial inner membrane organization system (MINOS) and Mia40 (reaction IIb). Imported apoSOD1 interacts with mature CCS through a transient intermolecular disulfide bond (reaction IIIa), which promotes the formation of the intramolecular disulfide and subsequent trapping of SOD1 in IMS. Folding of muSOD1 can happen via interaction with CCS or by yet poorly known mechanisms such as oxidization by H₂O₂ or protein disulfide isomerase (PDI)—type of oxidoreductase (IIIb). Alternatively, mutants unable to fold correctly may form oligomers in IMS (reaction IVb). The disulfide oxidized mature monomers form the active enzyme by dimerization (reaction IVa). In ALS, mutant and wt homodimers may co-exist with heterodimers. Mature dimeric SOD1 dismutates superoxide (O_2-) to O₂ and H₂O₂ (reaction Va). Alternatively, superoxide may react with CytC³⁺ which oxidizes it to O₂ (Vb). CytC³⁺ can also catalyze peroxidation in the presence of H₂O₂ yielding oxoferryl-cytC (CytCFe⁴⁺) which as a highly reactive oxidant may cause mitochondrial damage (reaction VI). The critical reactions (Va and VI) leading to mitochondrial damage are marked with bolded arrows.