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Inflammation is a cellular response to factors that challenge the homeostasis of cells and tissues. Cell-associated and soluble pattern-recognition receptors, e.g. Toll-like receptors, inflammasome receptors, and complement components initiate complex cellular cascades by recognizing or sensing different pathogen and damage-associated molecular patterns, respectively. Cytokines and chemokines represent alarm messages for leukocytes and once activated, these cells travel long distances to targeted inflamed tissues. Although it is a crucial survival mechanism, prolonged inflammation is detrimental and participates in numerous chronic age-related diseases. This article will review the onset of inflammation and link its functions to the pathogenesis of age-related macular degeneration (AMD), which is the leading cause of severe vision loss in aged individuals in the developed countries. In this progressive disease, degeneration of the retinal pigment epithelium (RPE) results in the death of photoreceptors, leading to a loss of central vision. The RPE is prone to oxidative stress, a factor that together with deteriorating functionality, e.g. decreased intracellular recycling and degradation due to attenuated heterophagy/autophagy, induces inflammation. In the early phases, accumulation of intracellular lipofuscin in the RPE and extracellular drusen between RPE cells and Bruch’s membrane can be clinically detected. Subsequently, in dry (atrophic) AMD there is geographic atrophy with discrete areas of RPE loss whereas in the wet (exudative) form there is neovascularization penetrating from the choroid to retinal layers. Elevations in levels of local and systemic biomarkers indicate that chronic inflammation is involved in the pathogenesis of both disease forms.

Age-related macular degeneration (AMD) is a complex, degenerative and progressive eye disease that usually does not lead to complete blindness, but can result in severe loss of central vision. Risk factors for AMD include age, genetics, diet, smoking, oxidative stress and many cardiovascular-associated risk factors. Autophagy is a cellular housekeeping process that removes damaged organelles and protein aggregates, whereas heterophagy, in the case of the retinal pigment epithelium (RPE), is the phagocytosis of exogenous photoreceptor outer segments. Numerous studies have demonstrated that both autophagy and heterophagy are highly active in the RPE. To date, there is increasing evidence that constant oxidative stress impairs autophagy and heterophagy, as well as increases protein aggregation and causes inflammasome activation leading to the pathological phenotype of AMD. This review ties together these crucial pathological topics and reflects upon autophagy as a potential therapeutic target in AMD.

Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is considered to be a key factor in age-related macular degeneration (AMD) pathology. RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. The ubiquitin-proteasome and the lysosomal/autophagy pathways are the two major proteolytic systems to remove damaged proteins and organelles. There is increasing evidence that proteostasis is disturbed in RPE as evidenced by lysosomal lipofuscin and extracellular drusen accumulation in AMD. Nuclear factor-erythroid 2-related factor-2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) are master transcription factors in the regulation of antioxidant enzymes, clearance systems, and biogenesis of mitochondria. The precise cause of RPE degeneration and the onset and progression of AMD are not fully understood. However, mitochondria dysfunction, increased reactive oxygen species (ROS) production, and mitochondrial DNA (mtDNA) damage are observed together with increased protein aggregation and inflammation in AMD. In contrast, functional mitochondria prevent RPE cells damage and suppress inflammation. Here, we will discuss the role of mitochondria in RPE degeneration and AMD pathology focused on mtDNA damage and repair, autophagy/mitophagy signaling, and regulation of inflammation. Mitochondria are putative therapeutic targets to prevent or treat AMD.

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IntroductionThe BCR/ABL gene is derived from the relocation of a portion of c-ABL gene from chromosome 9 to the portion of BCR gene locus on chromosome 22 (t(9;22), Philadelphia chromosome [Ph]) and is present in most chronic myeloid leukemia (CML) and in a cohort of acute lymphocytic leukemia (ALL) patients. 1 BCR/ABL oncogenic tyrosine kinase (a product of BCR/ABL chimeric gene) exhibits 2 complementary roles in cancer. The first and best-characterized is stimulation of signaling pathways that eventually induce growth factor independence and affect the adhesive and invasive capability of leukemia cells. The second is the modulation of responses to DNA damage, rendering cells resistant to genotoxic therapies and causing genomic instability. 2 Clinical observations and experimental findings suggest that BCR/ABL-induced genomic instability may lead to mutations and chromosomal translocations frequently observed during the transition from a relatively benign CML chronic phase (CML-CP) to an aggressive blast crisis (CML-BC). 3 In addition, genomic instability also is manifested by numerous mutations detected in the BCR/ABL gene encoding for resistance to imatinib mesylate (IM). 4 IM, a selective inhibitor of ABL kinase activity, revolutionized the treatment of BCR/ABL-positive leukemias. 5 Unfortunately, clinical and experimental observations reveal that resistance to IM is increasingly problematic. 4 Although the rate of progression of newly diagnosed CML-CP patients on IM is about 4% per year, IM resistance obscures this otherwise successful oncogenetargeted therapy. 6 BCR/ABL kinase mutations appear to be the most frequent cause of acquired resistance to IM; resistant cells also may exhibit genomic amplification of nonmutated BCR/ABL and BCR/ABL independence due to overexpression of LYN kinase. 4,7 Mutations also were detected in CML-CP patients before IM treatment, thus arguing for genetic instability early in the disease. Therefore, the BCR/ABL gene appears to be a casualty of genomic instability promoted by its own product-the BCR/ABL kinase.Mutations usually result from enhanced DNA damage and/or deregulated mechanisms responsible for DNA repair. 8,9 Much endogenous DNA damage arises from intermediates of oxygen reduction. Oxygen is metabolized inside the cell by a series of one-electron reductions with the generation of reactive and potentially damaging intermediates called reactive oxygen species (ROS), 10 primarily generated by the mitochondrial respiratory chain (MRC). 11 ROS units usually are short-lived and strike only molecules that are close in space and time, such as free nucleotides, which are subsequently incorporated into DNA during replication by unfaithful polymerases. 9 Examples of ROS derivatives include 7,8-dihydro-8-oxo-2Ј-deoxyguanosine (8-oxoG), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy), thymidine glycol, and 5-hydroxycytosine. 12 BCR/ABL-mediated generation of ROS by MRC 13 combined with aberrant regulation of DNA repair pathways 14 may contribute to the mutator phenotype displa...

Age-related macular degeneration (AMD) is a multi-factorial disease that is the leading cause of irreversible and severe vision loss in the developed countries. It has been suggested that the pathogenesis of dry AMD involves impaired protein degradation in retinal pigment epithelial cells (RPE). RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, DNA and lipids and evoke tissue deterioration during the aging process. The ubiquitin-proteasome pathway and the lysosomal/autophagosomal pathway are the two major proteolytic systems in eukaryotic cells. NRF-2 (nuclear factor-erythroid 2-related factor-2) and PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) are master transcription factors in the regulation of cellular detoxification. We investigated the role of NRF-2 and PGC-1α in the regulation of RPE cell structure and function by using global double knockout (dKO) mice. The NRF-2/PGC-1α dKO mice exhibited significant age-dependent RPE degeneration, accumulation of the oxidative stress marker, 4-HNE (4-hydroxynonenal), the endoplasmic reticulum stress markers GRP78 (glucose-regulated protein 78) and ATF4 (activating transcription factor 4), and damaged mitochondria. Moreover, levels of protein ubiquitination and autophagy markers p62/SQSTM1 (sequestosome 1), Beclin-1 and LC3B (microtubule associated protein 1 light chain 3 beta) were significantly increased together with the Iba-1 (ionized calcium binding adaptor molecule 1) mononuclear phagocyte marker and an enlargement of RPE size. These histopathological changes of RPE were accompanied by photoreceptor dysmorphology and vision loss as revealed by electroretinography. Consequently, these novel findings suggest that the NRF-2/PGC-1α dKO mouse is a valuable model for investigating the role of proteasomal and autophagy clearance in the RPE and in the development of dry AMD.

Chromosomal translocations are responsible for the appearance of oncogenes encoding fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGF␤R, TEL/TRKC(L), and NPM/ALK (6, 35). BCR/ABL is derived from relocation of the portion of the c-ABL gene from chromosome 9 to the portion of the BCR gene locus on chromosome 22 [t(9;22)] and is present in most chronic myelogenous leukemia (CML) patients and a cohort of acute lymphocytic leukemia (ALL) patients (11,19,64). TEL/ABL results from a t(9;12) translocation reported in ALL, acute myelogenous leukemia (AML), and atypical CML (35) and consists of the amino-terminal fragment of the TEL domain fused in-frame with exon 2 of ABL (24). TEL/JAK2 was characterized as a product of a t(9;12) translocation which includes the TEL oligomerization domain and JAK2 catalytic domain (37) and was found in ALL (37, 51). TEL/PDGF␤R is associated with a t(5;12) translocation which juxtaposes the amino-terminal region of TEL with the transmembrane and tyrosine kinase domains of the platelet-derived growth factor receptor ␤ (23). TEL/PDGF␤R was found in chronic myelomonocytic leukemia (35). The consequence of t(12;15) is expression of the TEL/TRKC fusion tyrosine kinase associated with AML, infantile fibrosarcoma, and congenital mesoblastic nephroma (41). The TEL/TRKC fusion in AML [TEL/TRKC(L)] includes exons 1 to 4 of the TEL gene fused in frame to the tyrosine kinase domain of TRKC lacking a 42-bp exon near the C terminus of the TRKC moiety. NPM/ALK, formed by the t(2;5) translocation, was implicated in the pathogenesis of anaplastic large cell lymphoma (38). The NPM/ALK fusion gene encodes a 75-kDa hybrid protein that contains the aminoterminal portion of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase ALK (anaplastic lymphoma kinase) (44). These FTKs (BCR/ABL-related FTKs) show structural similarities, which include an amino-terminal oligomerization domain responsible for constitutive oligomerization and activation of the associated tyrosine kinase of the carboxy-terminal fusion partner.FTKs and other oncogenic tyrosine kinases such as v-Src and HER-2/neu activate multiple signaling pathways responsible for protection from apoptosis, induction of growth factor-independent proliferation, transformation, and resistance to therapeutic drugs and to ␥-radiation (25,41,43,53,54,61,85). Resistance to DNA-damaging agents is a cause for failure in the therapy of human cancer, including hematological malignancies. Several mechanisms of resistance to DNA damage