Cardiolipin and phosphatidylglycerol are not required for the in vivo action of Bcl-2 family proteins

Polčic, Peter; Su, Xiao; Fowlkes, Jonathan; Blachly-Dyson, Elizabeth; Dowhan, William; Forte, Michael

doi:10.1038/sj.cdd.4401566

Cited by 21 publications

(18 citation statements)

References 29 publications

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“…SMAC was used as a control as it is not affected by salt concentration Cardiolipin or MTCH2 can serve as tBID receptors E Raemy et al such compensatory mechanisms, as previous experiments showed that PG cannot substitute for CL in the regulation of MOMP. 13,27 In contrast, MTCH2, which has previously been reported to act as a tBID receptor, 29,41 could compensate for the CL deficit. In favor of this hypothesis, we observed an effect of MTCH2 depletion on tBID recruitment in cells depleted of CL (Figures 5a and b), suggesting that CL and MTCH2 may have compensatory roles in directly binding and recruiting tBID to the MOM, an idea already proposed by others.…”

Section: Discussionmentioning

confidence: 87%

“…Indeed, it has been shown that CL is not essential for BAX-mediated MOMP in this organism. 25,27 Additional studies in mammalian cells and liposomes have also questioned a specific requirement for CL in MOMP. 26,28 Some authors even showed increased kinetics of apoptosis in cells with less CL.…”

Section: Discussionmentioning

confidence: 99%

“…23,24 Despite these observations, other studies have questioned the requirement for CL in apoptosis and MOMP, and have suggested that CL is much less important for tBID-induced BAX activation than previously anticipated. [25][26][27][28] In addition, it has been recently shown that MTCH2, a transmembrane protein of the MOM, can also act as a receptor for tBID in the mitochondria during apoptosis. 29 To investigate the function of CL during apoptosis, we have generated a derivative of the human colorectal cancer cell line HCT116, in which we have deleted the cardiolipin synthase (CLS1) gene.…”

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confidence: 99%

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Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

et al. 2016

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During apoptosis, proapoptotic BAX and BAK trigger mitochondrial outer membrane (MOM) permeabilization by a mechanism that is not yet fully understood. BH3-only proteins such as tBID, together with lipids of the MOM, are thought to play a key role in BAX and BAK activation. In particular, cardiolipin (CL) has been shown to stimulate tBID-induced BAX activation in vitro. However, it is still unclear whether this process also relies on CL in the cell, or whether it is more dependent on MTCH2, a proposed receptor for tBID present in the MOM. To address this issue, we deleted both alleles of cardiolipin synthase in human HCT116 cells by homologous recombination, which resulted in a complete absence of CL. The CL-deficient cells were fully viable in glucose but displayed impaired oxidative phosphorylation and an inability to grow in galactose. Using these cells, we found that CL was not required for either tBID-induced BAX activation, or for apoptosis in response to treatment with TRAIL. Downregulation of MTCH2 in HCT116 cells also failed to prevent recruitment of tBID to mitochondria in apoptotic conditions. However, when both CL and MTCH2 were depleted, a significant reduction in tBID recruitment was observed, suggesting that in HCT116 cells, CL and MTCH2 can have redundant functions in this process.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

et al. 2016

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“…However, as discussed above, it is possible that in yeast, PG, which accumulates in the absence of CL synthase, compensates for the loss of CL. It still awaits clarification whether CL or its PG precursor are needed, for Bax to release cytochrome c [92]. This is particularly interesting since hydrophobic and electrostatic interactions make a different contribution to the binding of cytochrome c to CL or PG [93].…”

Section: Cardiolipin Redistributionmentioning

confidence: 99%

Cardiolipin: Setting the beat of apoptosis

2007

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Cardiolipin (CL) is a mitochondria-specific phospholipid which is known to be intimately linked with the mitochondrial bioenergetic machinery. Accumulating evidence now suggests that this unique lipid also has active roles in several of the mitochondria-dependant steps of apoptosis. CL is closely associated with cytochrome c at the outer leaflet of the mitochondrial inner membrane. This interaction makes the process of cytochrome c release from mitochondria more complex than previously assumed, requiring more than pore formation in the mitochondrial outer membrane. While CL peroxidation could be crucial for enabling cytochrome c dissociation from the mitochondrial inner membrane, cytochrome c itself catalyzes CL peroxidation. Moreover, peroxy-CL directly activates the release of cytochrome c and other apoptogenic factors from the mitochondria. CL is also directly involved in mitochondrial outer membrane permeabilization by enabling docking and activation of proapoptotic Bcl-2 proteins. It appears therefore that CL has multiple roles in apoptosis and that CL metabolism contributes to the complexity of the apoptotic process.

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“…32 These observations are in accordance with a recent study demonstrating that cardiolipin is not required for the killing of yeast cells by the overexpression of Bax. 33 …”

Section: Interaction Of Cytochrome C With Cardiolipinmentioning

confidence: 99%