Memeli hücrelerinde otofajinin moleküler mekanizması

Abstract

Mayadan insana kadar evrimsel olarak korunmuş bir mekanizma olan makrootofaji (bundan sonra otofaji), hücreleri açlıktan ve buna bağlı streslerden korumakta ve makromolekülleri enerji sağlamak için kullanılabilecek olan yapı taşlarına indirgemektedir. Otofaji, bir parça sitoplazma yığınını, organelleri (örneğin mitokondri ve peroksizomlar), agregat oluşturmaya eğilim gösteren proteinleri ve enfeksiyöz ajanları otofagozomlar olarak adlandırılan çift-membranlı veziküllerle lizozomlara taşıyan hücre içi degredasyon yoludur. Memeli sistemi üzerine yapılan çalışmalar, sağlık ve hastalıkta otofajinin diğer önemli rollerini göstermiştir. Klinik öncesi hem nörodejeneratif hem de enfeksiyöz hastalıklarla ilgili hayvan modellerinde yapılan araştırmalar, otofaji upregülasyonunun, demans formları (tau'nun neden olduğu), Parkinson hastalığı (α-sinüklein) ve Huntington hastalığı (mutant huntingtin) gibi çeşitli nörodejeneratif hastalıklara neden olan agregata eğilimli intrasitoplazmik proteinlerin degradasyonunda; Salmonella typhi ve Mycobacterium tuberculosis gibi patojenik ajanlardan kaynaklanan belli bulaşıcı hastalıklara karşı korunmada önemli bir rol oynadığını göstermiştir. Fare hematopoietik kök hücrelerin (HSCs) devamlılığının sürdürülmesinde gerekliliği vurgulanan otofaji, fonksiyonelliği bozulduğunda HSC'leri normalden pre-lökemik bir duruma geçirmektedir. Mutasyonlar veya önemli otofaji regülatörlerinin ifadelerinin azalması nedeniyle otofajik aktivitede gerçekleşen düşüş, pre-lösemi gelişimini desteklerken, bu mekanizmanın tedavide kullanılan ajanlarla yeniden etkinleştirilmesi hastalığın nüksetmesine yol açmaktadır. Otofaji aktivasyon düzeyi, kanser progresyonu ile anabolik ve katabolik işlemlerde üstlendiği rollerden dolayı obezite ve metabolik hastalıklarda önemli rol oynamaktadır. Otofajinin sağlıkta ve çeşitli hastalıkların patogenezindeki moleküler mekanizmalarına ilişkin çalışmaların sayısı gün geçtikçe artmaktadır. Bu derlemede, memeli hücrelerinde gerçekleşen otofaji ve moleküler mekanizması hakkında genel bir bakış sunulması ve bilgi verilmesi amaçlanmıştır.

Keywords

• otofaji,memeli hücresi,moleküler mekanizma

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