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Can a crowded mitochondrial membrane limit O2 uptake?

Can a crowded mitochondrial membrane limit O2 uptake?


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The mitochondrial inner membrane is crowded with proteins (electron transport chain complexes, ATPases, etc.). As the proteins are packed more and more densely in this membrane, the diffusion of any molecule through the membrane should decrease, since there are less "gaps" for it to go through. I have no idea if this effect is insignificant for the entry of O2 into the mitochondria.

So my question is: Can O2 entry into the mitochondria become limited due to the high density of proteins in the mitochondrial inner membrane?


Mitochondrial dysfunction is an early event in high-NaCl-induced apoptosis of mIMCD3 cells

Raising osmolality to 700 mosmol/kgH2O by the addition of NaCl rapidly kills most murine inner renal medullary collecting duct cells (mIMCD3), but they survive at 500 mosmol/kgH2O. At 300 and 500 mosmol/kgH2O, NADH autofluorescence is present in a mitochondria-associated, punctate perinuclear pattern. Within 45 s to 30 min at 700 mosmol/kgH2O, the autofluorescence spreads diffusely throughout the cell. This correlates with mitochondrial membrane depolarization, measured as decreased tetramethylrhodamine methyl ester perchlorate (TMRM) fluorescence. Mitochondrial dysfunction should increase the cellular ADP/ATP ratio. In agreement, this ratio increases within 1–6 h. Mitochondrial morphology (transmission electron microscopy) is unaffected, but nuclear hypercondensation becomes evident. Progressive apoptosis occurs beginning 1 h after osmolality is raised to 700, but not to 500, mosmol/kgH2O. General caspase activity and caspase-9 activity increase only after 6 h at 700 mosmol/kgH2O. The mitochondrial Bcl-2/Bax ratio decreases within 1–3 h, but no cytochrome c release is evident. The mitochondria contain little p53 at any osmolality. Adding urea to 700 mosmol/kgH2O does not change NADH or TMRM fluorescence. We conclude that extreme acute hypertonicity causes a mitochondrial dysfunction involved in the initiation of apoptosis.

during the production of concentrated urine, cells of the renal medulla experience osmotic concentrations of NaCl in the interstitium exceeding 1,000 mosmol/kgH2O (8), which they survive. In contrast, renal medullary cells in tissue culture die rapidly by apoptosis after acute addition of NaCl that raises the osmolality above 600 mosmol/kgH2O (35, 45). Mitochondria are known to play a pivotal role in triggering and coordinating apoptosis (24), making this organelle a logical candidate to evaluate in NaCl-induced apoptosis in mIMCD3 cells.

Hypertonicity, induced by high NaCl, decreases cell volume, increases cytosolic osmolality, and changes mitochondrial osmotic equilibrium, which could affect mitochondrial function. Mitochondria normally have a high negative membrane potential that provides a driving force for entry of cations from the cytoplasm. Resulting net uptake of cations by mitochondria, followed by osmotic swelling, constitutes a threat to their osmotic integrity. Mitochondrial volume is normally maintained by the kinetic equilibrium between electrophoretic K + entry and electroneutral K + efflux via the K + /H + antiporter (10, 23). The influence of matrix volume on mitochondrial metabolism has been studied in isolated mitochondria in vitro. Experiments designed to alter matrix volume demonstrate strong effects on mitochondrial metabolism (2, 26, 40). Acute hypertonic stress inhibits substrate oxidation, reduces respiration, and decreases ATPase activity (3, 17, 18, 26, 34, 37, 40). The time course of these changes depends on the nature and concentration of the osmolyte used to increase tonicity, and the changes are reversible below 500 mosmol/kgH2O (10, 17, 18). These observations could be relevant to the mechanism of hypertonicity-induced apoptosis. Mitochondria can initiate apoptosis when, for example, drugs or chemical agents depolarize their membranes, uncouple respiration, and inhibit ATP synthesis.

Mitochondrial membrane potential is a good indicator of their energy status, reflecting proton electrochemical gradient across the inner membrane. A decrease in membrane potential is associated with the release of apoptogenic factors from the mitochondria, and in several models of apoptosis is the first index of mitochondrial dysfunction (16). Members of the Bcl-2 family of proteins participate in the changes of the mitochondrial membrane permeability involved in the collapse of membrane potential and the release of apoptogenic factors. Bcl-2 is normally present in mitochondria and functions as a repressor of apoptosis (43, 53). Bax, a proapoptotic Bcl-2 family member, is a soluble protein predominantly present in the cytosol (11, 21, 25, 29). During the induction of apoptosis, Bax shifts to membranes, including those in mitochondria. Furthermore, Bax and Bcl-2 mutually antagonize each other when coexpressed in the same cell, and the ratio of Bcl-2/Bax in mitochondria determines the cellular response to death signals transmitted by mitochondria (16, 39, 50). Inhibition of apoptosis by Bcl-2 may result from homodimerization or oligomerization with Bax, maintenance of mitochondrial homeostasis resulting in prevention of apoptogenic factors release, and/or inhibition of the production of reactive oxygen species (1, 25, 54, 55).

In view of these considerations, we hypothesized that acute hypertonic stress in mIMCD3 cells might critically affect mitochondrial function. Thus the resultant apoptosis could be the consequence of mitochondrial dysfunction, possibly involving changes in the Bcl-2/Bax ratio and the release of apoptogenic signaling molecules from mitochondria. We tested our hypothesis by measuring mitochondrial function and apoptosis in mIMCD3 cells stressed by addition of NaCl to the medium. A combination of biochemical and morphological methods was used to characterize changes in mitochondrial structure and the localization of cytochrome c, Bax, Bcl-2, and p53.


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