In VivoPathogenic Role of Mutant SOD1 Localized in the Mitochondrial Intermembrane Space

Abstract

Mutations in Cu,Zn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 causes a complex array of pathological events, through toxic gain of function mechanisms, leading to selective motor neuron degeneration. Mitochondrial dysfunction is among the well-established toxic effects of mutant SOD1, but its mechanisms are just starting to be elucidated. A portion of mutant SOD1 is localized in mitochondria, where it accumulates mostly on the outer membrane and inside the intermembrane space (IMS). Evidence in cultured cells suggests that mutant SOD1 in the IMS causes mitochondrial dysfunction and compromises cell viability. Therefore, to test its pathogenic role in vivo we generated transgenic mice expressing G93A mutant or wild type (WT) human SOD1 targeted selectively to the mitochondrial IMS (mito-SOD1). We show that mito-SOD1 is correctly localized in the IMS, where it oligomerizes and acquires enzymatic activity. Mito-G93ASOD1 mice, but not mito-WTSOD1 mice, develop a progressive disease characterized by body weight loss, muscle weakness, brain atrophy, and motor impairment, which is more severe in females. These symptoms are associated with reduced spinal motor neuron counts and impaired mitochondrial bioenergetics, characterized by decreased cytochrome oxidase activity and defective calcium handling. However, there is no evidence of muscle denervation, a cardinal pathological feature of ALS. Taken together, our findings indicate that mutant SOD1 in the mitochondrial IMS causes mitochondrial dysfunction and neurodegeneration, but per se it is not sufficient to cause a full-fledged ALS phenotype, which requires the participation of mutant SOD1 localized in other cellular compartments.

Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD

“…Mitochondria in the spinal cord are well-known to be a target in motor neuron diseases (32) and both CCS and SOD enter as metal-deficient forms in the mitochondrial intermembrane space in SOD-transgenic mice (33–37). This mitochondrial-localized fraction of SOD with CCS should be particularly effective at competing with cytochrome c oxidase for copper and potentially can contribute to the accelerated death of SOD G93A xCCS mice.…”

Mitochondrial Dysfunction in Neurodegenerative Diseases

“…Furthermore, mislocalization of mitochondria at synapses among motor neurons in vitro correlates with abnormal synaptic number, structure, and function (Magrané et al, 2012). Expressing mutant SOD1 confined to mitochondria is sufficient to produce loss of motor neurons and an ALS phenotype (Igoudjil et al, 2011).…”

Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis

“…In mitochondria, SOD1 localizes in the intermembrane space (IMS) and can be protective from superoxide produced locally (Kawamata and Manfredi, 2008; Vijayvergiya et al, 2005). However, accumulation of mutant SOD1 in the IMS can cause havoc (Igoudjil et al, 2011; Magrane et al, 2009; Son et al, 2008; Son et al, 2007) and mitochondrial proteins can be abnormally oxidized (Mattiazzi et al, 2002). Furthermore, increased superoxide generation through NADPH oxidase (NOX) activity in mutant SOD1 microglia have been demonstrated (Harraz et al, 2008; Marden et al, 2007).…”