In vivo induced deletion of the mitochondrial protein stomatin-like protein-2 is associated with development of an inflammatory motor deficit disorder (54.10)

Abstract

Abstract Stomatin-like protein (SLP)-2 is a mainly mitochondrial protein identified in proteome analysis of glycolipid-enriched membrane microdomains of mammalian cells, including lymphocytes. Our preliminary data suggest SLP-2 recruits prohibitins to cardiolipin-enriched domains in the mitochondrial inner membrane to form specialized membrane microdomains, required for optimal cellular respiration. We hypothesized that deletion of the SLP-2 gene will cause defective mitochondrial function that may result in organ-selective disease. We found that a conventional SLP-2-deficient mouse was embryonic lethal at the pre-implantation stage. Thus we generated viable tamoxifen-inducible systemic SLP-2 knockout mice. Administration of tamoxifen (3mg/40g; 10 days; i.p.) resulted in a motor phenotype characterized by poorer SHIRPA scores, weight loss and death (68% at day 28, p<0.05). This phenotype correlated with SLP-2 gene deletion and decreased protein levels in select tissues. Histological analysis revealed multifocal myofibrillar degeneration of the diaphragm with a mononuclear inflammatory infiltrate. In addition, apoptosis throughout the exocrine pancreas and pancreatic atrophy due to loss of normal acinar tissue were observed. In conclusion, in vivo SLP-2 deletion induces a mitochondrial disease-like phenotype, suggesting this protein is required for optimal metabolic function. SLP-2-deficient mice may be useful to assess the function of SLP-2 in vivo and to study mitochondrial diseases.