Lipids of mitochondria

Daum, Günther

doi:10.1016/0304-4157(85)90002-4

Cited by 797 publications

(430 citation statements)

References 337 publications

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“…29 In the plasma membrane, cholesterol has the well-known capacity to induce formation of ordered microdomains, characterized by their resistance to detergent-induced solubilization. Some mitochondrial proteins were recently reported to remain insoluble under similar conditions, suggesting that analogous lipid rafts might be present in mitochondrial membranes.…”

Section: Discussionmentioning

confidence: 99%

Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes

2007

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Activation of Bax or Bak is essential for the completion of many apoptotic programmes. Under cytotoxic conditions, these proteins undergo a series of conformational rearrangements that end up with their oligomerization. We found that unlike inactive monomeric Bax, active oligomerized Bax is partially resistant to trypsin digestion, providing a convenient read out to monitor Bax activation. Using this assay, we studied how the lipid composition of membranes affects tBid-induced Bax activation in vitro with pure liposomes. We report that Bax activation is inhibited by cholesterol and by decreases in membrane fluidity. This observation was further tested in vivo using the drug U18666A, which we found increases mitochondrial cholesterol levels. When incubated with tBid, mitochondria isolated from U18666A-treated cells showed a delay in the release of Smac/Diablo and Cytochrome c, as well as in Bax oligomerization. Moreover, pre-incubation with U18666A partially protected cells from stressinduced apoptosis. As many tumours display high mitochondrial cholesterol content, inefficient Bax oligomerization might contribute to their resistance to apoptosis-inducing agents. Among the stimuli that lead to apoptosis, a series of stress conditions trigger the permeabilization of the mitochondrial outer membrane (MOM) and the release of pro-apoptotic factors that will activate caspases in the cytosol. This so-called intrinsic apoptotic pathway is tightly regulated by proteins of the Bcl-2 family, among which the pro-apoptotic members Bax and Bak are essential. They seem to be the central players whose activation results in MOM permeabilization.Under resting conditions, whereas Bak essentially resides in the MOMs, Bax is found in loose association with membranes (mainly the MOMs) or as a soluble protein in the cytosol. Following many cytotoxic signals, Bax and Bak undergo a series of conformational rearrangements. 1 Bax translocates to mitochondria and inserts into the MOMs in a form that cannot be detached by alkali treatment. Bax and Bak then uncover N-terminal epitopes and oligomerize. Oligomerization, shown by size exclusion chromatography, 2 crosslinking experiments 3,4 and native gel electrophoresis, 5 appears as the critical step resulting in MOM permeabilization. However, despite many efforts, it remains unclear how each of these conformational rearrangements is regulated, and how Bax/Bak oligomerization leads to the release of mitochondrial apoptogenic factors. Both processes are undoubtedly regulated by other members of the Bcl-2 family, 6,7 but the participation of many unrelated proteins was also proposed. 8 While a BH3-only protein appears to be sufficient for Bax to oligomerize in synthetic liposomes, 9,10 additional proteins could be required for its activation in isolated mitochondria. 11 These might directly interact with Bax, and/or modify the membrane properties to allow its oligomerization. Interaction with mitochondrial lipids is indeed an important parameter to consider as the final conformational rearrange...

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Section: Discussionmentioning

confidence: 99%

Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes

2007

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“…It is not yet possible to make conclusive generalization how any changes in FA profile in cellular membrane component could influence cellular functions. However, it is possible that the changes in membrance FA composition actually could occur under various conditions and affect cellular functions (DAUM, 1985;SPECTOR and YOREK, 1985). The changes observed here may reflect certain modifications in the metabolic activity of skeletal muscles as well as BAT induced by cold acclimation.…”

Section: Discussionmentioning

confidence: 99%

Muscle and brown adipose tissue fatty acid profiles in cold-exposed rats.

1987

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Effects of cold acclimation and cold exposure for 25 generations on triglyceride (TG)-, total phospholipid (PL)-, and cardiolipin (CL)-fatty acid (FA) compositions were studied in the different types of skeletal muscles (red and white muscles from quadriceps, and soleus) as well as brown adipose tissue (BAT) in rats. TG: in cold-acclimated rats (CA) and rats reared in cold for 25 generations (25G) white muscle showed the decreased saturated FA (SA) and increased polyunsaturated FA (PU). In soleus of 25G, monounsaturated FA (MU) and PU increased, and SA decreased. In BAT, SA increased and MU decreased in CA, and SA and PU decreased, and MU increased in 25G. PL: in red muscle of CA, SA increased and PU decreased. In red muscle of 25G the similar but more marked changes were found accompanied by lowered arachidonic acid and unsaturation index (UI). In BAT, SA, PU, arachidonic acid, and UI increased in CA, and arachidonic acid increased in 25G. CL: in red and white muscles of 25G, oleic acid and MU increased. In BAT, arachidonic acid increased in CA and 25G, and UI increased in 25G. These results suggest that FA unsaturation of CL in the muscles as well as BAT is involved in an enhanced thermogenesis in cold-exposed rats.

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“…Mitochondrial membranes differ from other cellular membranes in that they contain a high proportion of cardiolipin (CL), about 10-20% [52]. Cardiolipin provides essential structural and functional support to a number of proteins involved in mitochondrial bioenergetics, and confers fluidity and stability to the mitochondrial membrane [53,54].…”

Section: Synuclein Binds To Purified Mitochondria At Low Phmentioning

confidence: 99%

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

Cole

DiEuliis

Leo

et al. 2008

Experimental Cell Research

179

164

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Mitochondrial dysfunction plays a central role in the selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) and is influenced by both environmental and genetic factors. Expression of the PD protein α-synuclein or its familial mutants often sensitizes neurons to oxidative stress and to damage by mitochondrial toxins. This effect is thought to be indirect, since little evidence physically linking α-synuclein to mitochondria has been reported. Here, we show that the distribution of α-synuclein within neuronal and non-neuronal cells is dependent on intracellular pH. Cytosolic acidification induces translocation of α-synuclein from the cytosol onto the surface of mitochondria. Translocation occurs rapidly under artificially-induced low pH conditions and as a result of pH changes during oxidative or metabolic stress. Binding is likely facilitated by low pH-induced exposure of the mitochondria-specific lipid cardiolipin. These results imply a direct role for α-synuclein in mitochondrial physiology, especially under pathological conditions, and in principle, link α-synuclein to other PD genes in regulating mitochondrial homeostasis.

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Lipids of mitochondria

Cited by 797 publications

References 337 publications

Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes

Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes

Muscle and brown adipose tissue fatty acid profiles in cold-exposed rats.

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

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