Autophagy: a cellular stres and a cell death mechanism (Otofaji: bir hücresel stres yanıtı ve ölüm mekanizması)

Autophagy is a physiological phenomenon responsible for the degradation of long-lived proteins, organelles and cytoplasmic fragments. It allows cellular recycling following lysosomal degradation and helps the cell to survive various stress conditions including starvation, growth factor and oxidative stress. Paradoxically, under certain conditions autophagy may kill the cell through a caspase-independent, non-apoptotic type of cell death (Type II cell death or autophagic cell death). Several lines of evidence point out to a direct connection between classical apoptosis and autophagy. Molecular mechanisms of apoptosis-autophagy connection start to be unraveled. The cross-talk between autophagy and apoptosis seems quite complex but certainly is critical for the development of novel diagnosis, follow-up and treatment modalities in health problems such as cancer, infections and neurodegenerative diseases

Autophagy: a cellular stres and a cell death mechanism

Autophagy is a physiological phenomenon responsible for the degradation of long-lived proteins, organelles and cytoplasmic fragments. It allows cellular recycling following lysosomal degradation and helps the cell to survive various stress conditions including starvation, growth factor and oxidative stress. Paradoxically, under certain conditions autophagy may kill the cell through a caspase-independent, non-apoptotic type of cell death (Type II cell death or autophagic cell death). Several lines of evidence point out to a direct connection between classical apoptosis and autophagy. Molecular mechanisms of apoptosis-autophagy connection start to be unraveled. The cross-talk between autophagy and apoptosis seems quite complex but certainly is critical for the development of novel diagnosis, follow-up and treatment modalities in health problems such as cancer, infections and neurodegenerative diseases

Cleavage of Atg3 protein by caspase-8 regulates autophagy during receptor-activated cell death

Autophagy is an evolutionarily conserved mechanism contributing to cell survival under stress conditions including nutrient and growth factor deprivation. Connections and cross-talk between cell death mechanisms and autophagy is under investigation. Here, we describe Atg3, an essential regulatory component of autophagosome biogenesis, as a new substrate of caspase-8 during receptor-mediated cell death. Both, TNF-α- (tumor necrosis factor α) and TRAIL- (tumor necrosis factor-related apoptosis inducing ligand) induced cell death was accompanied by Atg3 cleavage and this event was inhibited by a pan-caspase inhibitor (zVAD) or a caspase-8-specific inhibitor (zIETD). Indeed, caspase-8 overexpression led to Atg3 degradation and this event depended on caspase-8 enzymatic activity. Mutation of the caspase-8 cleavage site on Atg3 abolished its cleavage both in vitro and in vivo, demonstrating that Atg3 was a direct target of caspase-8. Autophagy was inactive during apoptosis and blockage of caspases or overexpression of a non-cleavable Atg3 protein reestablished autophagic activity upon death receptor stimulation. In this system, autophagy was important for cell survival since inhibition of autophagy increased cell death. Therefore, Atg3 provides a novel link between apoptosis and autophagy during receptor-activated cell death

Mitochondria-Targeted Liposomes for Drug Delivery to Tumor Mitochondria

The special bilayer structure of mitochondrion is a promising therapeutic target in the diagnosis and treatment of diseases such as cancer and metabolic diseases. Nanocarriers such as liposomes modified with mitochondriotropic moieties can be developed to send therapeutic molecules to mitochondria. In this study, DSPE-PEG-TPP polymer conjugate was synthesized and used to prepare mitochondria-targeted liposomes (TPPLs) to improve the therapeutic index of chemotherapeutic agents functioning in mitochondria and reduce their side effects. Doxorubicin (Dox) loaded-TPPL and non-targeted PEGylated liposomes (PPLs) were prepared and compared based on physicochemical properties, morphology, release profile, cellular uptake, mitochondrial localization, and anticancer effects. All formulations were spherically shaped with appropriate size, dispersity, and zeta potential. The stability of the liposomes was favorable for two months at 4 °C. TPPLs localize to mitochondria, whereas PPLs do not. The empty TPPLs and PPLs were not cytotoxic to HCT116 cells. The release kinetics of Dox-loaded liposomes showed that Dox released from TPPLs was higher at pH 5.6 than at pH 7.4, which indicates a higher accumulation of the released drug in the tumor environment. The half-maximal inhibitory concentration of Dox-loaded TPPLs and PPLs was 1.62-fold and 1.17-fold lower than that of free Dox due to sustained drug release, respectively. The reactive oxygen species level was significantly increased when HCT116 cells were treated with Dox-loaded TPPLs. In conclusion, TPPLs may be promising carriers for targeted drug delivery to tumor mitochondria