BIO SEMINAR:Modeling and Alleviating Mitochondrial Myopathy...

Guest: Şükrü Anıl Doğan

Title:Modeling and Alleviating Mitochondrial Myopathy in Mice

Time: April 1, 2024, 13:00 

Location: FENS L055

Abstract:The adaptability of skeletal muscle mitochondria to various stressors and stimuli is well-known as these organelles are highly dynamic. However, when faced with severe and sustained mitochondrial dysfunction, these mechanisms are insufficient, leading to mitochondrial myopathies that cause significant muscular dysfunction.Mitochondrial aspartyl-tRNA synthetase (DARS2) is an essential enzyme responsible for the initial step of mitochondrial protein synthesis, attaching aspartate to its cognate tRNA. To investigate the impact of DARS2 deficiency on skeletal muscle, we generated a mouse model with muscle-specific deletion of DARS2 (mKO) using the CRE recombinase under the human skeletal muscle-specific α-actin (ACTA1) promoter. mKO mice displayed severe muscle dysfunction and a median survival of 54 days, with both males and females ceasing weight gain after weaning. Their fat and muscle mass were significantly lost at the end of their lives. Additionally, treadmill, activity cage, and grip strength tests revealed decreased locomotor activity and motor coordination in mKO mice, with the treadmill test showing a gradual decline over time, indicating a progressive mitochondrial myopathy.There is currently no cure for mitochondrial myopathy, but supportive methods have proven to be effective in alleviating the manifestation of the disorder. Following characterization, we focused on the therapeutic effects of the Ketogenic Diet (KD) and 5-Aminoimidazole-4-Carboxamide Ribonucleoside (AICAR) in mKO mice. Both KD and AICAR treatments partially rescued some of the molecular markers of myopathy; however, failed to alleviate the phenotype of the mKO mice. To summarize, we have generated a mitochondrial translation-deficient myopathy model, which mimics the clinical signs of mitochondrial myopathy. This mouse model provides a valuable tool for studying potential interventions to mitigate the myopathy phenotype.

Bio: Dr. Şükrü Anıl Doğan received his Bachelor’s and Master’s degrees from Middle East Technical University, Department of Molecular Biology and Genetics. With a passion for unraveling the intricacies of mitochondrial biology and its implications in aging and age-related diseases, Dr. Doğan moved to Cologne, Germany, where he pursued his Ph.D. at CECAD. Afterwards, Dr. Doğan worked as an Investigator Scientist at MRC Mitochondrial Biology Unit, University of Cambridge on reactive oxygen species signaling in mitochondrial diseases. He returned to Turkey to establish his own research laboratory at Boğaziçi University, exploring the critical role of mitochondria in health and disease. Since then, Dr. Doğan has received numerous awards and grants, including EMBO Installation Grant, The Science Academy, Turkey’s Young Scientist Award, YÖK Research Universities Support Program Grant, and Boğaziçi University’s Excellence in Teaching Award.