Autophagy is a process in which a cell eats its own contents (Greek: auto, self; phagy, eating). It involves the delivery of cytoplasmic materials to the lysosome for degradation. Depending on how the material is delivered, autophagy can be categorized into three types:

• Chaperone-mediated autophagy (direct translocation across the lysosomal membrane by chaperone proteins)

• Microautophagy (inward invagination of lysosomal membrane for delivery)

• Macroautophagy (hereafter referred to as autophagy), the major form of autophagy involving the sequestration and transportation of portions of cytosol in a doublemembrane bound autophagic vacuole (autophagosome)

Autophagy is seen in single-celled organisms as well as mammalian cells. It is an evolutionarily conserved survival mechanism whereby, in states of nutrient deprivation, the starved cell lives by cannibalizing itself and recycling the digested contents. Autophagy is implicated in many physiologic states (e.g., aging and exercise) and pathologic processes. It proceeds through several steps (Fig. 1):

• Formation of an isolation membrane, also called phagophore, and its nucleation; the isolation membrane is believed to be derived from the ER

• Elongation of the vesicle

• Maturation of the autophagosome, its fusion with lysosomes, and eventual degradation of the contents

Fig1. Autophagy. Cellular stresses, such as nutrient deprivation, activate an autophagy pathway that proceeds through several phases (initiation, nucleation, and elongation of isolation membrane) and eventually creates double-membrane-bound vacuoles (autophagosome) in which cytoplasmic materials including organelles are sequestered and then degraded following fusion of the vesicles with lysosomes. In the final stage, the digested materials are released for recycling of metabolites. See text for details. (Modified from Choi, AMK, Ryter S, Levine B: Autophagy in human health and disease. N Engl J Med 368:651, 2013.)

In recent years, more than a dozen “autophagy-related genes” called Atgs have been identified whose products are required for the creation of the autophagosome. While the details of the process are still not fully understood, its outlines have been defined. In a simple model, environmental cues like starvation or depletion of growth factors activate an initiation complex of four proteins that stimulates the assembly of a nucleation complex. This in turn promotes the nucleation of the autophagosomal

membrane. The autophagosomal membrane elongates further, surrounds and captures its cytosolic cargo, and closes to form the autophagosome. The elongation and closure of the autophagosomal membrane requires the coordinated action of several ubiquitin-like conjugation systems, including the microtubule-associated protein light chain 3 (LC3). The synthesis of LC3 is augmented during autophagy and it is therefore a useful marker for identifying cells in which autophagy is occurring. The newly formed autophagosome fuses with endosomes and then finally with lysosomes to form an autophagolysosome. In the terminal step, the inner membrane and enclosed cytosolic cargoes are degraded by lysosomal enzymes. There is some evidence that autophagy is not a random process that engulfs cytosolic contents indiscriminately. Instead, it appears that the loading of cargo into the autophagosome is “selective” and that one of the functions of the LC3 system is to “target” protein aggregates and effete organelles.

Autophagy functions as a survival mechanism under various stress conditions, maintaining the integrity of cells by recycling essential metabolites and clearing cellular debris. It is therefore prominent in atrophic cells, which are exposed to severe nutrient deprivation. Autophagy is also involved in the turnover of organelles like ER, mitochondria, and lysosomes and the clearance of intracellular aggregates that accumulate during aging, stress and various other diseases states. Autophagy can trigger cell death if it is inadequate to cope with the stress imposed on the cell. This pathway of cell death is distinct from necrosis and apoptosis, but the mechanism is unknown. Furthermore, it is not clear whether cell death is caused by autophagy or by the stress that triggered autophagy. Nevertheless, autophagic vacuolization often precedes or accompanies cell death.

There is increasing evidence that autophagy plays a role in human diseases. Some examples are listed:

• Cancer: This is an area of active investigation and as discussed in Chapter 7, autophagy can both promote cancer growth and act as a defense against cancers.

• Neurodegenerative disorders: Many neurodegenerative disorders are associated with dysregulation of autophagy. In Alzheimer disease, formation of autophagosomes is accelerated and in mouse models genetic defects in autophagy accelerate neurodegeneration. In Huntington disease, mutant huntingtin impairs autophagy.

• Infectious diseases: Many pathogens are degraded by autophagy; these include mycobacteria, Shigella spp., and HSV-1. This is one way by which microbial proteins are digested and delivered to antigen presentation pathways. Macrophage-specific deletion of Atg5 increases susceptibility to tuberculosis.

• Inflammatory bowel diseases: Genome-wide association studies have linked both Crohn disease and ulcerative colitis to SNPs in autophagy related genes.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم شؤون المعارف يطلق دورة (صفات الشيعة) لعدد من ملاكات العتبة العباسية المقدسة

الهيأة العليا لإحياء التراث تبحث تعزيز التعاون المشترك مع مركز الإمام الباقر (عليه السلام) في إيران

جامعة الكفيل تكرِّم طلبتها المتميزين من ذوي الاحتياجات الخاصة

فريق طبي في مستشفى الكفيل يجري عملية ناجحة لطفل يعاني من تشوّه ولاديّ بالنخاع الشوكي

المزيد

الآخبار الصحية

خصوصا مع تقدم السن.. 6 سلوكيات يومية قد تدمّر صحتك

فاكهة خضراء.. علاج طبيعي فعّال للإمساك واضطرابات الهضم

روسيا تبدأ أولى التجارب السريرية للقاح واعد ضد السرطان

كنز غذائي على طبقك.. ماذا تفعل السبانخ بجسمك؟

المزيد

الآخبار التكنلوجية

رصد نوع نادر من القطط في تايلاند للمرة الأولى منذ عقود

روسيا تخطط لإقامة محطة نووية في القمر خلال العقد المقبل

كيف قاد إيلون ماسك حملة "غروك" لاختراق عرش الذكاء الاصطناعي

ألتمان: الذكاء الاصطناعي سيتجاوز البشر في 2026 !

المزيد

مواضيع ذات صلة

Frontotemporal and Vascular Dementias

Alzheimer’s Disease

Human Prion Diseases

Diabetes treatments

Preeclampsia and Eclampsia

Gestational Diabetes

Clinical Manifestations of Aging and Hematopoiesis

Reactions of Blood Vessels in Acute Inflammation

Cellular Aging

Pathologic Calcification

Acute Lymphoblastic Leukemia

Myelodysplastic Syndromes