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SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse.

ABSTRACT: Motor axon degeneration is a critical but poorly understood event leading to weakness and muscle atrophy in motor neuron diseases. Here, we investigated oxidative stress-mediated axonal degeneration in mice lacking the antioxidant enzyme, Cu,Zn superoxide dismutase (SOD1). We demonstrate a progressive motor axonopathy in these mice and show that Sod1(-/-) primary motor neurons extend short axons in vitro with reduced mitochondrial density. Sod1(-/-) neurons also show oxidation of mitochondrial--but not cytosolic--thioredoxin, suggesting that loss of SOD1 causes preferential oxidative stress in mitochondria, a primary source of superoxide in cells. SOD1 is widely regarded as the cytosolic isoform of superoxide dismutase, but is also found in the mitochondrial intermembrane space. The functional significance of SOD1 in the intermembrane space is unknown. We used a transgenic approach to express SOD1 exclusively in the intermembrane space and found that mitochondrial SOD1 is sufficient to prevent biochemical and morphological defects in the Sod1(-/-) model, and to rescue the motor phenotype of these mice when followed to 12 months of age. These results suggest that SOD1 in the mitochondrial intermembrane space is fundamental for motor axon maintenance, and implicate oxidative damage initiated at mitochondrial sites in the pathogenesis of motor axon degeneration.

SUBMITTER: Fischer LR

PROVIDER: S-EPMC3009841 | biostudies-other | 2011 Jan

REPOSITORIES: biostudies-other

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SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse.

Fischer Lindsey R LR Igoudjil Anissa A Magrané Jordi J Li Yingjie Y Hansen Jason M JM Manfredi Giovanni G Glass Jonathan D JD

Brain : a journal of neurology 20101114 Pt 1

Motor axon degeneration is a critical but poorly understood event leading to weakness and muscle atrophy in motor neuron diseases. Here, we investigated oxidative stress-mediated axonal degeneration in mice lacking the antioxidant enzyme, Cu,Zn superoxide dismutase (SOD1). We demonstrate a progressive motor axonopathy in these mice and show that Sod1(-/-) primary motor neurons extend short axons in vitro with reduced mitochondrial density. Sod1(-/-) neurons also show oxidation of mitochondrial-- ...[more]

PMID: 21078595

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Project description:Mitochondria are quantitatively the most important sources of reactive oxygen species (ROS) which are formed as by-products during cellular respiration. ROS generation occurs when single electrons are transferred to molecular oxygen. This leads to a number of different ROS types, among them superoxide. Although most studies focus on ROS generation in the mitochondrial matrix, the intermembrane space (IMS) is also important in this regard. The main scavengers for the detoxification of superoxide in the IMS are Cu, Zn superoxide dismutase (SOD1) and cytochrome-c. Similar to ROS, certain reactive carbonyl species are known for their high reactivity. The consequences are deleterious modifications to essential components compromising cellular functions and contributing to the etiology of severe pathological conditions like cancer, diabetes and neurodegeneration. In this study, we investigated the susceptibility of SOD1 and cytochrome-c to in vitro glycation by the dicarbonyl methylglyoxal (MGO) and the resulting effects on their structure. We utilized experimental techniques like immunodetection of the MGO-mediated modification 5-hydro-5-methylimidazolone, differential scanning calorimetry, fluorescence emission and circular dichroism measurements. We found that glycation of cytochrome-c leads to monomer aggregation, an altered secondary structure (increase in alpha helical content) and slightly more compact folding. In addition to structural changes, glycated cytochrome-c displays an altered thermal unfolding behavior. Subjecting SOD1 to MGO does not influence its secondary structure. However, similar to cytochrome-c, subunit aggregation is observed under denaturating conditions. Furthermore, the appearance of a second peak in the calorimetry diagram indirectly suggests de-metallation of SOD1 when high MGO levels are used. In conclusion, our data demonstrate that MGO has the potential to alter several structural parameters in important proteins of energy metabolism (cytochrome-c) and antioxidant defense (cytochrome-c, SOD1).

Project description:BACKGROUND:The proteome of mitochondria comprises mostly proteins that originate as precursors in the cytosol. Before import into the organelle, such proteins are exposed to cytosolic quality control mechanisms. Multiple lines of evidence indicate a significant contribution of the major cytosolic protein degradation machinery, the ubiquitin-proteasome system, to the quality control of mitochondrial proteins. Proteins that are directed to the mitochondrial intermembrane space (IMS) exemplify an entire class of mitochondrial proteins regulated by proteasomal degradation. However, little is known about how these proteins are selected for degradation. RESULTS:The present study revealed the heterogeneous cytosolic stability of IMS proteins. Using a screening approach, we found that different cytosolic factors are responsible for the degradation of specific IMS proteins, with no single common factor involved in the degradation of all IMS proteins. We found that the Cox12 protein is rapidly degraded when localized to the cytosol, thus providing a sensitive experimental model. Using Cox12, we found that lysine residues but not conserved cysteine residues are among the degron features important for protein ubiquitination. We observed the redundancy of ubiquitination components, with significant roles of Ubc4 E2 ubiquitin-conjugating enzyme and Rsp5 E3 ubiquitin ligase. The amount of ubiquitinated Cox12 was inversely related to mitochondrial import efficiency. Importantly, we found that precursor protein ubiquitination blocks its import into mitochondria. CONCLUSIONS:The present study confirms the involvement of ubiquitin-proteasome system in the quality control of mitochondrial IMS proteins in the cytosol. Notably, ubiquitination of IMS proteins prohibits their import into mitochondria. Therefore, ubiquitination directly affects the availability of precursor proteins for organelle biogenesis. Importantly, despite their structural similarities, IMS proteins are not selected for degradation in a uniform way. Instead, specific IMS proteins rely on discrete components of the ubiquitination machinery to mediate their clearance by the proteasome.

Dataset Information

SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse.

Publications

SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse.

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