Browsing by Subject "Mitochondria"

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Open Access
ER Stress-induced sphingosine-1-phosphate lyase phosphorylation potentiates the mitochondrial unfolded protein response
(American Society for Biochemistry and Molecular Biology Inc., 2022-10) Yıldırım, Aslı Dilber; Citir, Mevlut; Doğan, Aslı Ekin; Veli, Zehra; Yıldırım, Zehra; Tufanli, Ozlem; Traynor-Kaplan, Alexis; Schultz, Carsten; Erbay, Ebru
The unfolded protein response (UPR) is an elaborate signaling network that evolved to maintain proteostasis in the endoplasmic reticulum (ER) and mitochondria (mt). These organelles are functionally and physically associated, and consequently, their stress responses are often intertwined. It is unclear how these two adaptive stress responses are coordinated during ER stress. The inositol-requiring enzyme-1 (IRE1), a central ER stress sensor and proximal regulator of the UPRER, harbors dual kinase and endoribonuclease (RNase) activities. IRE1 RNase activity initiates the transcriptional layer of the UPRER, but IRE1’s kinase substrate(s) and their functions are largely unknown. Here, we discovered that sphingosine 1-phosphate (S1P) lyase (SPL), the enzyme that degrades S1P, is a substrate for the mammalian IRE1 kinase. Our data show that IRE1-dependent SPL phosphorylation inhibits SPL’s enzymatic activity, resulting in increased intracellular S1P levels. S1P has previously been shown to induce the activation of mitochondrial UPR (UPRmt) in nematodes. We determined that IRE1 kinase-dependent S1P induction during ER stress potentiates UPRmt signaling in mammalian cells. Phosphorylation of eukaryotic translation initiation factor 2α (eif2α) is recognized as a critical molecular event for UPRmt activation in mammalian cells. Our data further demonstrate that inhibition of the IRE1-SPL axis abrogates the activation of two eif2α kinases, namely double-stranded RNA-activated protein kinase (PKR) and PKR–like ER kinase upon ER stress. These findings show that the IRE1-SPL axis plays a central role in coordinating the adaptive responses of ER and mitochondria to ER stress in mammalian cells. © 2022 THE AUTHORS.
Open Access
PACT establishes a posttranscriptional brake on mitochondrial biogenesis by promoting the maturation of miR-181c
(American Society for Biochemistry and Molecular Biology Inc., 2022-07) Doğan, Aslı Ekin; Hamid, Syed M.; Yıldırım, Aslı Dilber; Yıldırım, Zehra; Sen, Ganes; Riera, Celine E.; Gottlieb, Roberta A.; Erbay, Ebru
The double-stranded RNA-dependent protein kinase activating protein (PACT), an RNA-binding protein that is part of the RNA-induced silencing complex, plays a key role in miR-mediated translational repression. Previous studies showed that PACT regulates the expression of various miRs, selects the miR strand to be loaded onto RNA-induced silencing complex, and determines proper miR length. Apart from PACT's role in mediating the antiviral response in immune cells, what PACT does in other cell types is unknown. Strikingly, it has also been shown that cold exposure leads to marked downregulation of PACT protein in mouse brown adipose tissue (BAT), where mitochondrial biogenesis and metabolism play a central role. Here, we show that PACT establishes a posttranscriptional brake on mitochondrial biogenesis (mitobiogenesis) by promoting the maturation of miR-181c, a key suppressor of mitobiogenesis that has been shown to target mitochondrial complex IV subunit I (Mtco1) and sirtuin 1 (Sirt1). Consistently, we found that a partial reduction in PACT expression is sufficient to enhance mitobiogenesis in brown adipocytes in culture as well as during BAT activation in mice. In conclusion, we demonstrate an unexpected role for PACT in the regulation of mitochondrial biogenesis and energetics in cells and BAT. © 2022 The Authors
Open Access
Targeted photosensitizers and controlled singlet oxygen generation for therapeutic applications
(2018-12) Uçar, Esma
Photodynamic therapy of cancer plays a pivotal role due to its many superior features and potential. Considering the pathways for improving the practice of PDT of cancer is gradually increasing, enhancing the selectivity of photodynamic action is an obvious choice. Being the source of reactive oxygen species in the body, mitochondrion is one of the most proper organelles to target. There is plethora of findings suggesting that triphenlyphosphonium cation is a very favorable mitochondria targeting agent. Another aspect of PDT requires creation of smart molecules which respond to either the increased temperature or ion concentrations in order to release 1O2. Cyclic endoperoxides of naphthalene and anthracene could help in achieving the desired objective of storing 1O2 and regenerating it again when appropriate conditions meet. The half-life cycloreversion of 1,4-Dimethylnaphthalene could be changed at least 100-fold when 2-position of the naphthalene is sterically hindered. Taking advantage of the fact that fluoride ions’ silicophile nature, a novel perspective for drug design can be proposed. In the final project, a certain level magnetic hyperthermia, large enough to cause endoperoxide cycloreversion, but not large enough to cause necrotic death, is being sought after. Controlled generation singlet oxygen by the application of tissue penetrating alternating magnetic fields is the ultimate goal for that project.