A big picture of the mitochondria-mediated signals: From mitochondria to organism.

Mitochondria, well-known for years as the powerhouse and biosynthetic center of the cell, are dynamic signaling organelles beyond their energy production and biosynthesis functions. The metabolic functions of mitochondria, playing an important role in various biological events both in physiological and stress conditions, transform them into important cellular stress sensors. Mitochondria constantly communicate with the rest of the cell and even from other cells to the organism, transmitting stress signals including oxidative and reductive stress or adaptive signals such as mitohormesis. Mitochondrial signal transduction has a vital function in regulating integrity of human genome, organelles, cells, and ultimately organism.

The bridge between cell survival and cell death: reactive oxygen species-mediated cellular stress.

As a requirement of aerobic metabolism, regulation of redox homeostasis is indispensable for the continuity of living homeostasis and life. Since the stability of the redox state is necessary for the maintenance of the biological functions of the cells, the balance between the pro-oxidants, especially ROS and the antioxidant capacity is kept in balance in the cells through antioxidant defense systems. The pleiotropic transcription factor, Nrf2, is the master regulator of the antioxidant defense system. Disruption of redox homeostasis leads to oxidative and reductive stress, bringing about multiple pathophysiological conditions. Oxidative stress characterized by high ROS levels causes oxidative damage to biomolecules and cell death, while reductive stress characterized by low ROS levels disrupt physiological cell functions. The fact that ROS, which were initially attributed as harmful products of aerobic metabolism, at the same time function as signal molecules at non-toxic levels and play a role in the adaptive response called mithormesis points out that ROS have a dose-dependent effect on cell fate determination. See also Figure 1(Fig. 1).

An investigation of different intracellular parameters for Inborn Errors of Metabolism: Cellular stress, antioxidant response and autophagy.

Oxidative stress is associated with various disease pathologies including Inborn Errors of Metabolism (IEMs), among the most important causes of childhood morbidity and mortality. At least as much as oxidative stress in cells, reductive stress poses a danger to the disruption of cell homeostasis. p62/SQSTM1, protects cells from stress by activation of Nrf2/Keap1 and autophagy pathways. In this study, we tested the role of cellular stress, mitochondrial dysfunction and autophagy via Nrf2/Keap1/p62 pathway in the pathophysiology of three main groups of IEMs. Our results showed that antioxidant and oxidant capacity alone would not be sufficient to reflect the true clinical picture of these diseases. ATP, ROS and mitochondrial membrane potantial (MMP) measurements demonstrated increased cellular stress and bioenergetic imbalance in methylmalonic acidemia (MMA), indicating mild mitochondrial dysfunction. In isovaleric acidemia (IVA), no major change was detected in ATP, ROS and MMP values. Propionic acidemia (PA), mitochondrial diseases (MIT) and mucopolysaccharidosis IV (MPS IV) might point out mitohormesis to cope with chronic reductive stress. Induction of Nrf2/Keap1/p62 pathway and increased expression of HMOX1 were detected in all IEMs. LC3B-II and p62 expression results indicated an impaired autophagic flux in MIT and MPS IV and an induction of autophagic flux in MMA, PA and IVA, but also partial expression of Beclin1, enables autophagy activation, was detected in all IEMs. We conclude that individual diagnosis and treatments are of great importance in IEMs. In addition, we assume that the application of therapeutic antioxidant or preventive treatments without determining the cellular stress status in IEMs may disrupt the sensitive oxidant-antioxidant balance in the cell, leading to the potential to further disrupt the clinical picture, especially in patients with reductive stress. To the best of our knowledge, this is the first study to simultaneously relate IEMs with cellular stress, mitochondrial dysfunction, and autophagy.

Rare occurrence of common filaggrin mutations in Turkish children with food allergy and atopic dermatitis

Background/aim: Filaggrin is a protein complex involved in epidermal differentiation and skin barrier formation. Mutations of the filaggrin gene (FLG) are associated with allergen sensitization and allergic diseases like atopic dermatitis (AD), allergic rhinitis, food allergy (FA), and asthma. The aim of the study is to reveal the frequency of change in the FLG gene and determine the association between FLG loss-of-function (LOF) mutations and FA and/or AD in Turkish children. Materials and methods: Four FLG loss-of-function (LOF) mutations known to be common in European populations were analyzed in 128 healthy children, 405 food-allergic children with or without atopic dermatitis, and 61 children with atopic dermatitis. PCR-RFLP was performed for genotyping R501X, 2282del4, and R2447X mutations; S3247Xwas genotyped using a TaqMan-based allelic discrimination assay. Results were confirmed by DNA sequence analysis in 50 randomly chosen patients for all mutations. Results: A total of 466 patients [(67% male, 1 (0.7­2.8) years] and 128 healthy controls [59% male, 2.4 (1.4­3.5) years)] were included in this study. Two patients were heterozygous carriers of wild-type R501X, but none of the controls carried this mutation. Three patients and one healthy control were heterozygous carriers of wild-type 2282del4. Neither patients nor controls carried R2447X or S3247X FLGmutations. There were no combined mutations determined in heterozygous mutation carriers. Conclusions: Although R501X, 2282del4, R2447X, and S3247X mutations are very common in European populations, we found that FLG mutations were infrequent and there is no significant association with food allergy and/or atopic dermatitis in Turkish individuals.