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Mitochondrial membrane biogenesis: phospholipids and proteins go hand in hand.

Gohil VM, Greenberg ML - J. Cell Biol. (2009)

Bottom Line: Brügger, B.Westermann, and T.Langer. 2009.

View Article: PubMed Central - PubMed

Affiliation: Massachusetts General Hospital Center for Human Genetic Research, Boston, MA 02114, USA.

ABSTRACT
Mitochondrial membrane biogenesis requires the import and synthesis of proteins as well as phospholipids. How the mitochondrion regulates phospholipid levels and maintains a tight protein-to-phospholipid ratio is not well understood. Two recent papers (Kutik, S., M. Rissler, X.L. Guan, B. Guiard, G. Shui, N. Gebert, P.N. Heacock, P. Rehling, W. Dowhan, M.R. Wenk, et al. 2008. J. Cell Biol. 183:1213-1221; Osman, C., M. Haag, C. Potting, J. Rodenfels, P.V. Dip, F.T. Wieland, B. Brügger, B. Westermann, and T. Langer. 2009. J. Cell Biol. 184:583-596) identify novel regulators of mitochondrial phospholipid biosynthesis. The biochemical approach of Kutik et al. (2008) uncovered an unexpected role of the mitochondrial translocator assembly and maintenance protein, Tam41, in the biosynthesis of cardiolipin (CL), the signature phospholipid of mitochondria. The genetic analyses of Osman et al. (2009) led to the discovery of a new class of mitochondrial proteins that coordinately regulate CL and phosphatidylethanolamine, another key mitochondrial phospholipid. These elegant studies highlight overlapping functions and interdependent roles of mitochondrial phospholipid biosynthesis and protein import and assembly.

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Identification of novel regulators of mitochondrial nonbilayer-forming phospholipids. (A) Interdependence of CL biosynthesis and function. Four enzymatic steps catalyze CL biosynthesis in the inner mitochondrial membrane (IMM). The genes encoding three steps have been identified. Import machinery for proteins with N-terminal cleavable sequences (Tim23) or internal signals (Tim22) is also localized in the IMM. The newly identified Tam41 regulates Tim23- and Tim22-dependent protein import as well as CL biosynthesis, possibly by activating Cds1. CL, in turn, regulates protein import by maintaining the IMM potential by a mechanism not currently understood. CL stabilizes supercomplex assembly of complex III and IV, and stimulates complex IV activity. The pH gradient generated by respiratory chain activity increases CL synthesis by activating Crd1 synthase activity. (B) Genetic interactome of prohibitins regulates PE and/or CL levels. Genes identified in a synthetic genetic screen as genetic interactors of prohibitins (Phb1/2) consist of three classes that regulate (1) CL levels, (2) PE levels, or (3) both CL and PE. CDP-DG, cytidine diphosphodiacylglycerol; CL, cardiolipin; PA, phosphatidic acid; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGP, phosphatidylglycerolphosphate.
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fig1: Identification of novel regulators of mitochondrial nonbilayer-forming phospholipids. (A) Interdependence of CL biosynthesis and function. Four enzymatic steps catalyze CL biosynthesis in the inner mitochondrial membrane (IMM). The genes encoding three steps have been identified. Import machinery for proteins with N-terminal cleavable sequences (Tim23) or internal signals (Tim22) is also localized in the IMM. The newly identified Tam41 regulates Tim23- and Tim22-dependent protein import as well as CL biosynthesis, possibly by activating Cds1. CL, in turn, regulates protein import by maintaining the IMM potential by a mechanism not currently understood. CL stabilizes supercomplex assembly of complex III and IV, and stimulates complex IV activity. The pH gradient generated by respiratory chain activity increases CL synthesis by activating Crd1 synthase activity. (B) Genetic interactome of prohibitins regulates PE and/or CL levels. Genes identified in a synthetic genetic screen as genetic interactors of prohibitins (Phb1/2) consist of three classes that regulate (1) CL levels, (2) PE levels, or (3) both CL and PE. CDP-DG, cytidine diphosphodiacylglycerol; CL, cardiolipin; PA, phosphatidic acid; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGP, phosphatidylglycerolphosphate.

Mentions: CL, the signature phospholipid of the mitochondrion, is a dimeric phospholipid with the capacity to form nonbilayer structures in the presence of calcium ions. The CL biosynthetic pathway is well-characterized in Saccharomyces cerevisiae (see Fig. 1 A), and the availability of mutants of the genes encoding the CL biosynthetic enzymes has made in vivo studies of CL function possible. From yeast mutant studies, it is now clear that CL has diverse mitochondrial functions in respiratory chain supercomplex stabilization, mitochondrial protein import, ceramide synthesis, aging and apoptosis, and the translation of electron transport chain components (Joshi et al., 2009). Moreover, CL also affects cellular processes not previously associated with mitochondrial function, including cell wall and vacuolar biogenesis (Zhong et al., 2005; Chen et al., 2008). The significance of CL in human health is apparent from clinical studies showing that perturbation of CL metabolism leads to the life-threatening disorder known as Barth syndrome (Schlame and Ren, 2006).


Mitochondrial membrane biogenesis: phospholipids and proteins go hand in hand.

Gohil VM, Greenberg ML - J. Cell Biol. (2009)

Identification of novel regulators of mitochondrial nonbilayer-forming phospholipids. (A) Interdependence of CL biosynthesis and function. Four enzymatic steps catalyze CL biosynthesis in the inner mitochondrial membrane (IMM). The genes encoding three steps have been identified. Import machinery for proteins with N-terminal cleavable sequences (Tim23) or internal signals (Tim22) is also localized in the IMM. The newly identified Tam41 regulates Tim23- and Tim22-dependent protein import as well as CL biosynthesis, possibly by activating Cds1. CL, in turn, regulates protein import by maintaining the IMM potential by a mechanism not currently understood. CL stabilizes supercomplex assembly of complex III and IV, and stimulates complex IV activity. The pH gradient generated by respiratory chain activity increases CL synthesis by activating Crd1 synthase activity. (B) Genetic interactome of prohibitins regulates PE and/or CL levels. Genes identified in a synthetic genetic screen as genetic interactors of prohibitins (Phb1/2) consist of three classes that regulate (1) CL levels, (2) PE levels, or (3) both CL and PE. CDP-DG, cytidine diphosphodiacylglycerol; CL, cardiolipin; PA, phosphatidic acid; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGP, phosphatidylglycerolphosphate.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2654137&req=5

fig1: Identification of novel regulators of mitochondrial nonbilayer-forming phospholipids. (A) Interdependence of CL biosynthesis and function. Four enzymatic steps catalyze CL biosynthesis in the inner mitochondrial membrane (IMM). The genes encoding three steps have been identified. Import machinery for proteins with N-terminal cleavable sequences (Tim23) or internal signals (Tim22) is also localized in the IMM. The newly identified Tam41 regulates Tim23- and Tim22-dependent protein import as well as CL biosynthesis, possibly by activating Cds1. CL, in turn, regulates protein import by maintaining the IMM potential by a mechanism not currently understood. CL stabilizes supercomplex assembly of complex III and IV, and stimulates complex IV activity. The pH gradient generated by respiratory chain activity increases CL synthesis by activating Crd1 synthase activity. (B) Genetic interactome of prohibitins regulates PE and/or CL levels. Genes identified in a synthetic genetic screen as genetic interactors of prohibitins (Phb1/2) consist of three classes that regulate (1) CL levels, (2) PE levels, or (3) both CL and PE. CDP-DG, cytidine diphosphodiacylglycerol; CL, cardiolipin; PA, phosphatidic acid; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PGP, phosphatidylglycerolphosphate.
Mentions: CL, the signature phospholipid of the mitochondrion, is a dimeric phospholipid with the capacity to form nonbilayer structures in the presence of calcium ions. The CL biosynthetic pathway is well-characterized in Saccharomyces cerevisiae (see Fig. 1 A), and the availability of mutants of the genes encoding the CL biosynthetic enzymes has made in vivo studies of CL function possible. From yeast mutant studies, it is now clear that CL has diverse mitochondrial functions in respiratory chain supercomplex stabilization, mitochondrial protein import, ceramide synthesis, aging and apoptosis, and the translation of electron transport chain components (Joshi et al., 2009). Moreover, CL also affects cellular processes not previously associated with mitochondrial function, including cell wall and vacuolar biogenesis (Zhong et al., 2005; Chen et al., 2008). The significance of CL in human health is apparent from clinical studies showing that perturbation of CL metabolism leads to the life-threatening disorder known as Barth syndrome (Schlame and Ren, 2006).

Bottom Line: Brügger, B.Westermann, and T.Langer. 2009.

View Article: PubMed Central - PubMed

Affiliation: Massachusetts General Hospital Center for Human Genetic Research, Boston, MA 02114, USA.

ABSTRACT
Mitochondrial membrane biogenesis requires the import and synthesis of proteins as well as phospholipids. How the mitochondrion regulates phospholipid levels and maintains a tight protein-to-phospholipid ratio is not well understood. Two recent papers (Kutik, S., M. Rissler, X.L. Guan, B. Guiard, G. Shui, N. Gebert, P.N. Heacock, P. Rehling, W. Dowhan, M.R. Wenk, et al. 2008. J. Cell Biol. 183:1213-1221; Osman, C., M. Haag, C. Potting, J. Rodenfels, P.V. Dip, F.T. Wieland, B. Brügger, B. Westermann, and T. Langer. 2009. J. Cell Biol. 184:583-596) identify novel regulators of mitochondrial phospholipid biosynthesis. The biochemical approach of Kutik et al. (2008) uncovered an unexpected role of the mitochondrial translocator assembly and maintenance protein, Tam41, in the biosynthesis of cardiolipin (CL), the signature phospholipid of mitochondria. The genetic analyses of Osman et al. (2009) led to the discovery of a new class of mitochondrial proteins that coordinately regulate CL and phosphatidylethanolamine, another key mitochondrial phospholipid. These elegant studies highlight overlapping functions and interdependent roles of mitochondrial phospholipid biosynthesis and protein import and assembly.

Show MeSH
Related in: MedlinePlus