Mitochondrial membrane permeability

TBT and TFT are membrane-active molecules, and their mechanism of action appears to be strongly dependent on organotin(IV) lipophilicity. They function as ionophores and produce hemolysis, release Ca(II) from sarcoplasmic reticulum, alter phosphatodylseiine-induced histamine release, alter mitochondrial membrane permeability and perturb membrane enzymes. Organotin(IV) compounds have been shown to affect cell signaling they activate protein kinase and increase free arachidonic acid through the activation of phospholipase... 

Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process. In many cases proteins and/or lipid mediators that induce changes in mitochondrial membrane permeability and calcium regulation are produced or activated. For example, the pro-apoptotic Bcl-2 family members Bax, Bad and Bid may associate with the mitochondrial membrane and modify its permeability. Membrane-derived lipid mediators such as ceramide and 4-hydroxynonenal can also induce mitochondrial membrane alterations that are critical for the execution of apoptosis. 

The measurement of Em (A y) is also difficult.179 Three methods have been used (1) measurement with microelectrodes (2) observation of fluorescent probes (3) distribution of permeant ions. Microelectrodes inserted into mitochondria182 have failed to detect a significant value for Em. Fluorescent probes are not very reliable,179 183 leaving the distribution of permeant ions the method of choice. In this method a mitochondrial suspension is exposed to an ion that can cross the membrane but which is not pumped or subject to other influences that would affect its distribution. Under such conditions the ion will be distributed according to Eq. 18-11. The most commonly used ions are K+, the same ion that is thought to reflect the membrane potential of nerve axons (Chapter 30), or Rb+. To make the inner mitochondrial membrane permeable to K+, valinomycin (Fig. 8-22) is added. The membrane potential, with n = 1 in Eq. 9-1, becomes ... 

Iaccarino, I., Hancock, D., Evan, G., and Downward, J. (2003) c-Myc induces cytochrome c release in Rati fibroblasts by increasing outer mitochondrial membrane permeability in a Bid-dependent manner. Cell Death Differ. 10, 599-608. 

Question How does valinomycin render mitochondrial membranes permeable to K+ ... 

DCCD inhibits proton translocation through the F subunit of the ATP synthase. Thus, the value of A/xh increases to a point where proton translocation, and hence electron transport, becomes thermodynamically unfavorable. In addition, DCCD inactivates the ATP synthesis function of the ATP synthase. The uncoupler. 2,4-dinitrophenol, renders the inner mitochondrial membrane permeable to protons, leading to a decrease in the value of A/jih< and restoration of electron transport. However, 2,4-dinitrophenol cannot restore the activity of the DCCD-treated ATP synthase. 

Mitochondrial membrane permeability transition and its role in the mechanism of toxicity of many chemicals is a major area of research focus. The protein thiol status of mitochondria is crucial to the control of the inner-membrane potential for ATP synthesis and the membrane permeability transition as well as cellular integrity. Protein thiols appear to have a major role in signal transduction and are important in the responses to chemical exposure. 

Sustained elevations in intracellular Ca levels promote mitochondrial Ca uptake, which decreases the mitochondrial membrane potential and blocks the electron transport chain leading to ATP depletion. Large increases in mitochondrial Ca uptake also increase mitochondrial membrane permeability (Dubinsky and Levi, 1998) resulting in the release of proapoptotic factors such as cytochrome c and apoptosis inducing factor (AIL) (Luetjens et al, 2000). Cytochrome c binds to apoptotic protease-activation factor 1 (APAFl) and procaspase-9, forming a multiprotein complex known as the apoptosome that activates the caspase cascade. The apoptosome activates caspase-9, which in turn activates caspase-3. Caspase-3 activates caspase-activated DNase (CAD), resulting in DNA fragmentation, characteristic of apoptosis. 

Evidence accumulated over an involvement of indirect causes to cancer due to epigenetic alterations such as hyper- or hypo-methylation and CpG-island promoter region silencing, together with not strictly DNA-related effects (e.g., altered oxygen metabolism, oxidative stress, cell membrane disruption, or even mitochondrial membrane permeability transition induction) [22,28,29],... 

Increase in mitochondrial membrane permeability permeability transition pore opening (PT) decrease in mitochondrial membrane potential (MMP) JC-1 and JC-9 carbocyanine dyes Mito Tracker and MitoFluor dyes TMRME and Rhodamine 123 Flourescent probe, calcein redistribution Radiolabeled deoxyglucose Large changes may not be specifi for apoptosis subtle changes, more characteristic of apoptosis may not be measurable alterations may be reversible... 

Botla R, Spivey JR, Aguilar H, Bronk SF, Gores GJ (1995) Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glyche-nodeoxycholate a mechansism of UDCA cytoprotection. J Pharmacol Exp Ther 272 930-938... 

Certain poisons, called uncouplers, render the inner mitochondrial membrane permeable to protons. One example is the lipid-soluble chemical 2,4-dInItrophenol (DNP), which can reversibly bind and release protons and shuttle protons across the Inner membrane from the Intermembrane space Into the matrix. As a result, DNP dissipates the proton-motive... 

Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic infleimmation through activation of the irritant receptor TRPAl. Proc Natl Acad Sci USA 104 13519-13524 Tsujimoto Y, Shimizu S (2003) Role of the mitochondrial membrane permeability transition in cell death. Apoptosis 12 835-840... 

Townsend L, Ongjni E, Wenk G (2004) Novel therapeutic opportunities for Alzheimer s disease focus on nonsteroidal anti-inflammatory drugs. FASEB J 19 1592-1601 Trejo JL, Cairo E, Nunez A, Torres-Aleman 1 (2002) Sedentary hfe impairs self-reparative processes in the brain the role of serum insulin-like growth factor-1. Rev Neurosci 13 365-374 Tsuboi Y, Doh-ura K, Yamada T (2009) Continuous intraventricular infusion of pentosan polysulfate clinical trial against prion diseases. Neuropathology 29(5) 632-636 Tsujimoto Y, Shimizu S (2003) Role of the mitochondrial membrane permeability transition in cell death. Apoptosis 12 835-840... 

Figure 3. Schematic architecture of mitochondrial protein complexes. A transmembrane channel, called the permeability transition pore (FTP), is formed at the contaa sites between the inner and outer mitochondrial membrane (OM) of the mitochondria. The core components of PTP are the voltage-dependent anion channel (VDAC) in the outer membrane and the adenine nucleotide translocator (ANT) in the inner membrane (IM). VDAC allows diilusion of small molecules (<5 kDa), however ANT is only permeable to a few selected ions and metabolites and is responsible for maintaining the proton concentration gradient (pH) and the membrane elearic potential (A P,J. PTP is sometimes connected to destruction of permeability barrier and loss of the inner membrane potential and eventually results in mitochondrial membrane permeability transition during apoptosis and other specialized forms of cell death. Bax, Bak, Bc1-Xl and Bcl-2 locate in the outer membrane and may regulate the outer membrane permeability. The translocase of the outer membrane (TOM) and the translocase of the inner membrane (TlM) mediate protein import pathway in the mitochondria. Cy-D, cyclophilin D PBR, peripheral benzodiazepine receptor HK, hexokinase mtHSP70, mitochondrial heat shock protein 70.

Another promising biochemical approach, which may be linked to the deterioration of the hemopoitic system, involves the subcellular effects of lead on mitochondria. In experiments described by Brierley (2), lead at the micromolar level was shown to have a variety of effects centering around the inhibition of respiration and breakdown of the regulation of mitochondrial membrane permeability. The uptake of lead into the mitochondrial matrix is closely related to the membrane transport mechanism(s) for calcium. Since lead is known to inhibit several enzymes of the Kreb s cycle and the electron transport system, heme synthesis may be inhibited at the mitochon-... 

When apoptotic signaling reaches the mitochondria, mitochondrial membrane permeability is enhanced. 

Kurose etal. (1997) have examined the alteration of mitochondrial membrane potential (AWm) in rat hepatocytes exposed to ethanol using Rhl23 as an indicator of mitochondrial membrane potential. Acute ethanol administration significantly decreased AWm in hepatocytes within 30 min, suggesting that mitochondrial depolarisation is acutely observed as an early event of ethanol-induced hepatocyte injury. This phenomenon is known as the mitochondrial membrane permeability transition induced by the opening of the mitochondrial megachannel, also known as PT pore (Bernardi 1996). In a recent review, Adachi and ISHii (2002) addressed the mechanism of mitochondrial alterations and fiver injury induced by ethanol. 

These systems were studied for their mitochondrial membrane permeability (MMP) regulated by the mitochondrial permeability transition pore (MPT,... 

A balance between proapoptotic (BAX, BID, BAK, or BAD) and anti-apoptotic (Bcl-Xl and Bcl-2) members of the Bcl-2 family is recognized. The proapoptotic members are required to make the mitochondrial membrane permeable for the release of caspase activators such as cytochrome c. Control of proapoptotic proteins under normal cell conditions of non-apoptotic cells is incompletely understood, generally Bax or Bak are activated by the activation of BH3 proteins [23]. 

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