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Unveiling the last missing link of the cardiolipin synthetic pathway in mitochondria.

Tamura Y, Endo T - Aging (Albany NY) (2013)

View Article: PubMed Central - PubMed

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Mitochondria produce cellular energy ATP by using electrochemical energy stored as a proton gradient across the mitochondrial inner membrane (IM)... To generate the proton gradient, the respiratory-chain complexes in the IM pump up protons from the matrix to the inter-membrane space by coupling it to the electron transport through the respiratory chain... In the issue of Cell Metabolism (Volume 17, Issue 5, 709-718, 7 May 2013), we reported identification of Tam41 as a mitochondrial CDP-DAG synthase and the cellular system to compensate the loss of Tam41... Tam41 was originally identified as a protein important for assembly and maintenance of the TIM23 complex in the IM... However, a subsequent study showed that loss of Tam41 leads to significant decrease in CL and accumulation of PA, the precursor phospholipid of CDP-DAG... We observed generation of CDP-DAG upon incubation of wild-type Tam41, but not the Tam41 mutants, with fluorescence-labeled PA and CTP... These results demonstrate that Tam41 is a mitochondrial CDP-DAG synthase, which had been elusive previously (Figure 1)... Art5 is a member of the arrestin-related trafficking adaptor (ART) protein family and is known to facilitate degradation of inositol transporter in plasma membrane in response to exogenous inositol... Indeed, we found that growth defects of tam41Δ cells were restored in inositol-depleted media (Figure 1)... This observation also points to the fact that yeast cells have a backup system to tolerate the loss of Tam41... In relation to this, Connerth et al. showed that defects in cell growths and decrease in the CL level caused by the loss of Tam41 can be largely restored by the simultaneous loss of a PA transfer protein Ups1... This suggests the presence of an alternative CL synthetic pathway, which may be activated in the absence of both Tam41 and Ups1... These findings may offer hints about possible treatments of diseases and protection against aging processes associated with mitochondrial dysfunction arising from the compromised CL synthesis or CL oxidation.

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Roles of Tam41 and Art5 in yeast hospholipid biosynthetic pathwaysPM, plasma membrane; ER, endoplasmic reticulum; OM, mitochondrial outer embrane; IMS, mitochondrial intermembrane space; PS, phosphatidyl serine; PGP, phosphatidyl glycerol phosphate; PG, phosphatidyl glycerol.
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Figure 1: Roles of Tam41 and Art5 in yeast hospholipid biosynthetic pathwaysPM, plasma membrane; ER, endoplasmic reticulum; OM, mitochondrial outer embrane; IMS, mitochondrial intermembrane space; PS, phosphatidyl serine; PGP, phosphatidyl glycerol phosphate; PG, phosphatidyl glycerol.

Mentions: In the issue of Cell Metabolism (Volume 17, Issue 5, 709-718, 7 May 2013), we reported identification of Tam41 as a mitochondrial CDP-DAG synthase and the cellular system to compensate the loss of Tam41. Tam41 was originally identified as a protein important for assembly and maintenance of the TIM23 complex in the IM [4]. However, a subsequent study showed that loss of Tam41 leads to significant decrease in CL and accumulation of PA, the precursor phospholipid of CDP-DAG [5]. Besides, respiratory-chain super complexes tend to be destabilized in cells lacking Tam41, which indicates that the role of Tam41 is not limited to the TIM23 complex but to the protein complexes in the IM in general [5]. We thus reasoned that Tam41 could be a mitochondrial CDP-DAG synthase and asked whether Tam41 directly catalyzes the CDP-DAG formation. To this end, we purified Tam41 and its loss-of-function mutants from yeast cells and measured their CDP-DAG synthase activities in vitro. We observed generation of CDP-DAG upon incubation of wild-type Tam41, but not the Tam41 mutants, with fluorescence-labeled PA and CTP. These results demonstrate that Tam41 is a mitochondrial CDP-DAG synthase, which had been elusive previously (Figure 1).


Unveiling the last missing link of the cardiolipin synthetic pathway in mitochondria.

Tamura Y, Endo T - Aging (Albany NY) (2013)

Roles of Tam41 and Art5 in yeast hospholipid biosynthetic pathwaysPM, plasma membrane; ER, endoplasmic reticulum; OM, mitochondrial outer embrane; IMS, mitochondrial intermembrane space; PS, phosphatidyl serine; PGP, phosphatidyl glycerol phosphate; PG, phosphatidyl glycerol.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824408&req=5

Figure 1: Roles of Tam41 and Art5 in yeast hospholipid biosynthetic pathwaysPM, plasma membrane; ER, endoplasmic reticulum; OM, mitochondrial outer embrane; IMS, mitochondrial intermembrane space; PS, phosphatidyl serine; PGP, phosphatidyl glycerol phosphate; PG, phosphatidyl glycerol.
Mentions: In the issue of Cell Metabolism (Volume 17, Issue 5, 709-718, 7 May 2013), we reported identification of Tam41 as a mitochondrial CDP-DAG synthase and the cellular system to compensate the loss of Tam41. Tam41 was originally identified as a protein important for assembly and maintenance of the TIM23 complex in the IM [4]. However, a subsequent study showed that loss of Tam41 leads to significant decrease in CL and accumulation of PA, the precursor phospholipid of CDP-DAG [5]. Besides, respiratory-chain super complexes tend to be destabilized in cells lacking Tam41, which indicates that the role of Tam41 is not limited to the TIM23 complex but to the protein complexes in the IM in general [5]. We thus reasoned that Tam41 could be a mitochondrial CDP-DAG synthase and asked whether Tam41 directly catalyzes the CDP-DAG formation. To this end, we purified Tam41 and its loss-of-function mutants from yeast cells and measured their CDP-DAG synthase activities in vitro. We observed generation of CDP-DAG upon incubation of wild-type Tam41, but not the Tam41 mutants, with fluorescence-labeled PA and CTP. These results demonstrate that Tam41 is a mitochondrial CDP-DAG synthase, which had been elusive previously (Figure 1).

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Mitochondria produce cellular energy ATP by using electrochemical energy stored as a proton gradient across the mitochondrial inner membrane (IM)... To generate the proton gradient, the respiratory-chain complexes in the IM pump up protons from the matrix to the inter-membrane space by coupling it to the electron transport through the respiratory chain... In the issue of Cell Metabolism (Volume 17, Issue 5, 709-718, 7 May 2013), we reported identification of Tam41 as a mitochondrial CDP-DAG synthase and the cellular system to compensate the loss of Tam41... Tam41 was originally identified as a protein important for assembly and maintenance of the TIM23 complex in the IM... However, a subsequent study showed that loss of Tam41 leads to significant decrease in CL and accumulation of PA, the precursor phospholipid of CDP-DAG... We observed generation of CDP-DAG upon incubation of wild-type Tam41, but not the Tam41 mutants, with fluorescence-labeled PA and CTP... These results demonstrate that Tam41 is a mitochondrial CDP-DAG synthase, which had been elusive previously (Figure 1)... Art5 is a member of the arrestin-related trafficking adaptor (ART) protein family and is known to facilitate degradation of inositol transporter in plasma membrane in response to exogenous inositol... Indeed, we found that growth defects of tam41Δ cells were restored in inositol-depleted media (Figure 1)... This observation also points to the fact that yeast cells have a backup system to tolerate the loss of Tam41... In relation to this, Connerth et al. showed that defects in cell growths and decrease in the CL level caused by the loss of Tam41 can be largely restored by the simultaneous loss of a PA transfer protein Ups1... This suggests the presence of an alternative CL synthetic pathway, which may be activated in the absence of both Tam41 and Ups1... These findings may offer hints about possible treatments of diseases and protection against aging processes associated with mitochondrial dysfunction arising from the compromised CL synthesis or CL oxidation.

Show MeSH