Mitochondrial permeability transition involves dissociation of F1FO ATP synthase dimers and C-ring conformation

被引：168

作者：

Bonora, Massimo ^{[1
,2
]}

Morganti, Claudia ^{[1
,2
]}

Morciano, Giampaolo ^{[1
,2
]}

Pedriali, Gaia ^{[1
,2
]}

Lebiedzinska-Arciszewska, Magdalena ^{[3
]}

Aquila, Giorgio ^{[4
]}

Giorgi, Carlotta ^{[1
,2
]}

Rizzo, Paola ^{[4
]}

Campo, Gianluca ^{[5
]}

Ferrari, Roberto

Kroemer, Guido ^{[6
,7
,8
,9
,10
,11
,12
,13
]}

Wieckowski, Mariusz R. ^{[3
]}

Galluzzi, Lorenzo ^{[6
,14
]}

Pinton, Paolo ^{[1
,2
]}

机构：

[1] Univ Ferrara, Sect Gen Pathol, Dept Morphol Surg & Expt Med, Ferrara, Italy

[2] Univ Ferrara, Lab Technol Adv Therapies LTTA, Ferrara, Italy

[3] Nencki Inst Expt Biol, Dept Biochem, Warsaw, Poland

[4] Univ Ferrara, Dept Morphol Surg & Expt Med, Ferrara, Italy

[5] Univ Ferrara, Cardiovasc Inst, Ferrara, Italy

[6] Univ Paris Descartes Paris V, Paris, France

[7] Univ Pierre & Marie Curie Paris VI, Paris, France

[8] INSERM, U1138, Paris, France

[9] Ctr Rech Cordeliers, Equipe Labellisee Ligue Natl Canc 11, Paris, France

[10] Hop Europeen Georges Pompidou, AP HP, Pole Biol, Paris, France

[11] Metabol Platform, Gustave Roussy Canc Campus, Villejuif, France

[12] Cell Biol Platform, Gustave Roussy Canc Campus, Villejuif, France

[13] Karolinska Univ Hosp, Dept Womens & Childrens Hlth, Stockholm, Sweden

[14] Weill Cornell Med Coll, Dept Radiat Oncol, New York, NY 10065 USA

来源：

EMBO REPORTS | 2017年 / 18卷 / 07期

基金：

欧洲研究理事会;

关键词：

ATP synthasome; ATP5G1; cyclosporine A; CYPD; regulated necrosis; CYCLOPHILIN-D; CELL-DEATH; PORE; SUBUNIT; CRISTAE; DNA;

D O I：

10.15252/embr.201643602

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The impact of the mitochondrial permeability transition (MPT) on cellular physiology is well characterized. In contrast, the composition and mode of action of the permeability transition pore complex (PTPC), the supramolecular entity that initiates MPT, remain to be elucidated. Specifically, the precise contribution of the mitochondrial F1FO ATP synthase (or subunits thereof) to MPT is a matter of debate. We demonstrate that F1FO ATP synthase dimers dissociate as the PTPC opens upon MPT induction. Stabilizing F1FO ATP synthase dimers by genetic approaches inhibits PTPC opening and MPT. Specific mutations in the F1FO ATP synthase c subunit that alter C-ring conformation sensitize cells to MPT induction, which can be reverted by stabilizing F1FO ATP synthase dimers. Destabilizing F1FO ATP synthase dimers fails to trigger PTPC opening in the presence of mutants of the c subunit that inhibit MPT. The current study does not provide direct evidence that the C-ring is the long-sought pore-forming subunit of the PTPC, but reveals that PTPC opening requires the dissociation of F1FO ATP synthase dimers and involves the C-ring.

引用

页码：1077 / 1089

页数：13

共 43 条

[1]

Mitochondrial pH monitored by a new engineered green fluorescent protein mutant [J].