Mitochondrial ClpX Activates a Key Enzyme for Heme Biosynthesis and Erythropoiesis

被引：87

作者：

Kardon, Julia R. ^{[1
,7
]}

Yien, Yvette Y. ^{[2
]}

Huston, Nicholas C. ^{[2
]}

Branco, Diana S. ^{[2
]}

Hildick-Smith, Gordon J. ^{[2
]}

Rhee, Kyu Y. ^{[3
,4
]}

Paw, Barry H. ^{[2
,5
,6
]}

Baker, Tania A. ^{[1
,7
]}

机构：

[1] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Hematol,Dept Med, Boston, MA 02115 USA

[3] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA

[4] Weill Cornell Med Coll, Dept Med, Div Infect Dis, New York, NY 10065 USA

[5] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Hematol Oncol,Dept Med, Boston, MA 02115 USA

[6] Dana Farber Canc Inst, Dept Pediat, Boston, MA 02115 USA

[7] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA

来源：

CELL | 2015年 / 161卷 / 04期

基金：

巴西圣保罗研究基金会;

关键词：

5-AMINOLEVULINATE SYNTHASE; PYRIDOXAL KINASE; PORE LOOPS; PROTEIN; DEGRADATION; GENE; ORGANIZATION; RECOGNITION; HYDROLYSIS; DIAGNOSIS;

D O I：

10.1016/j.cell.2015.04.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The mitochondrion maintains and regulates its proteome with chaperones primarily inherited from its bacterial endosymbiont ancestor. Among these chaperones is the AAA+ unfoldase ClpX, an important regulator of prokaryotic physiology with poorly defined function in the eukaryotic mitochondrion. We observed phenotypic similarity in S. cerevisiae genetic interaction data between mitochondrial ClpX (mtClpX) and genes contributing to heme biosynthesis, an essential mitochondrial function. Metabolomic analysis revealed that 5-aminolevulinic acid (ALA), the first heme precursor, is 5-fold reduced in yeast lacking mtClpX activity and that total heme is reduced by half. mtClpX directly stimulates ALA synthase in vitro by catalyzing incorporation of its cofactor, pyridoxal phosphate. This activity is conserved in mammalian homologs; additionally, mtClpX depletion impairs vertebrate erythropoiesis, which requires massive upregulation of heme biosynthesis to supply hemoglobin. mtClpX, therefore, is a widely conserved stimulator of an essential biosynthetic pathway and uses a previously unrecognized mechanism for AAA+ unfoldases.

引用

页码：858 / 867

页数：10

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