Báo cáo khoa học: Estrogen-related receptor a and PGC-1-related coactivator constitute a novel

Estrogen-related receptor a and PGC-1-related coactivator

constitute a novel complex mediating the biogenesis of

functional mitochondria

Delphine Mirebeau-Prunier1–3, Soazig Le Pennec1,2, Caroline Jacques1,2, Naig Gueguen3

, Julie

Poirier1,2, Yves Malthiery1–3 and Fre´de´rique Savagner1–3

1 INSERM, UMR694, Angers, France

2 Universite´ d’Angers, France

3 CHU Angers, Laboratoire de Biochimie et Biologie mole´ culaire, France

Introduction

Mitochondrial biogenesis depends on nuclear tran￾scriptional factors to coordinate the transcriptional

machinery, and on transcriptional coactivators to inte￾grate environmental signals into this program of mito￾chondrial biogenesis. Most studies to date have

focused on changes in energy metabolic pathways that

Keywords

cell proliferation; estrogen-related receptor a;

mitochondrial biogenesis; PGC-1-related

coactivator; respiratory chain

Correspondence

D. Mirebeau-Prunier, INSERM, UMR 694,

CHU, 4 rue Larrey, 49033 Angers, France

Fax: +33 241 35 40 17

Tel: +33 241 35 33 14

E-mail: [email protected]

(Received 17 September 2009, revised 10

November 2009, accepted 25 November

2009)

doi:10.1111/j.1742-4658.2009.07516.x

Mitochondrial biogenesis, which depends on nuclear as well as mitochon￾drial genes, occurs in response to increased cellular ATP demand. The

nuclear transcriptional factors, estrogen-related receptor a (ERRa) and

nuclear respiratory factors 1 and 2, are associated with the coordination of

the transcriptional machinery governing mitochondrial biogenesis, whereas

coactivators of the peroxisome proliferator-activated receptor c coactiva￾tor-1 (PGC-1) family serve as mediators between the environment and this

machinery. In the context of proliferating cells, PGC-1-related coactivator

(PRC) is a member of the PGC-1 family, which is known to act in partner￾ship with nuclear respiratory factors, but no functional interference

between PRC and ERRa has been described so far. We explored three thy￾roid cell lines, FTC-133, XTC.UC1 and RO 82 W-1, each characterized by

a different mitochondrial content, and studied their behavior towards PRC

and ERRa in terms of respiratory efficiency. Overexpression of PRC and

ERRa led to increased respiratory chain capacity and mitochondrial mass.

The inhibition of ERRa decreased cell growth and respiratory chain capac￾ity in all three cell lines. However, the inhibition of PRC and ERRa pro￾duced a greater effect in the oxidative cell model, decreasing the

mitochondrial mass and the phosphorylating respiration, whereas the non￾phosphorylating respiration remained unchanged. We therefore hypothesize

that the ERRa–PRC complex plays a role in arresting the cell cycle

through the regulation of oxidative phosphorylation in oxidative cells, and

through some other pathway in glycolytic cells.

Abbreviations

COX, cytochrome c oxidase; CS, citrate synthase; Cyt c, cytochrome c somatic; ERE, estrogen response element; ERR, estrogen-related

receptor; ERRE, estrogen-related receptor response element; ERa, estrogen receptor a; FCCP, carbonyl cyanide p-trifluoromethoxyphenyl￾hydrazone; HIF, hypoxia-inducible factor; LDH, lactate dehydrogenase; mtDNA, mitochondrial DNA; NRF, nuclear respiratory factor; PGC-1,

peroxisome proliferator-activated receptor c coactivator-1; PPAR, peroxisome proliferator-activated receptor; PRC, PGC-1-related coactivator;

siRNA, short interfering RNA.

FEBS Journal 277 (2010) 713–725 ª 2010 The Authors Journal compilation ª 2010 FEBS 713