Role of the c subunit of the F<sub>O</sub>ATP synthase in mitochondrial permeability transition

Bonora, Massimo; Bononi, Angela; Marchi, Elena De; Giorgi, Carlotta; Lebiedzińska, Magdalena; Marchi, Saverio; Patergnani, Simone; Rimessi, Alessandro; Suski, Jan M.; Wojtala, Aleksandra; Wieckowski, Mariusz R.; Kroemer, Guido; Galluzzi, Lorenzo; Pinton, Paolo

doi:10.4161/cc.23599

Cited by 425 publications

(362 citation statements)

References 75 publications

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“…As previously observed, the OPCs exposed to TNF-a exhibited significantly reduced [Ca Alterations in the mitochondrial structure were evaluated using digital deconvolution microscopy in OPCs infected by an adenoviral vector carrying cDNA encoding a mitochondriatargeted green fluorescent protein (GFP). 19 The number and mean volume of mitochondria per cell were also determined for both TNF-a-exposed and control oligodendrocytes. Neither the total network volume nor the single particle volume was significantly different between the different experimental conditions (Figure 3c).…”

Section: Resultsmentioning

confidence: 99%

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

et al. 2014

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Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-a) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-a exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-a induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation.

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Section: Resultsmentioning

confidence: 99%

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

et al. 2014

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“…We demonstrated binding of Bcl-x L within F 1 to the beta-subunit of the ATP synthase, suggesting that the channel responsible for the leak conductance lies within the membrane portion (ATP synthase F O ) and that Bcl-x L binding to F 1 might close the leak. Recent studies also support the idea that the mPTP is located within the multiprotein-lipid complex of the ATP synthase (10,14,15); however, a review of these articles confirms that the specific protein responsible for pore formation remains undetermined (16). We now describe that the purified c-subunit of the mammalian ATP synthase, when reconstituted into liposomes, forms a voltage-dependent channel sensitive to adenine nucleotides, recombinant F 1 beta-subunit protein, and anti-csubunit antibodies.…”

mentioning

confidence: 86%

An uncoupling channel within the c-subunit ring of the F ₁ F _O ATP synthase is the mitochondrial permeability transition pore

Alavian

Beutner²,

Lazrove

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

518

543

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Mitochondria maintain tight regulation of inner mitochondrial membrane (IMM) permeability to sustain ATP production. Stressful events cause cellular calcium (Ca 2+ ) dysregulation followed by rapid loss of IMM potential known as permeability transition (PT), which produces osmotic shifts, metabolic dysfunction, and cell death. The molecular identity of the mitochondrial PT pore (mPTP) was previously unknown. We show that the purified reconstituted c-subunit ring of the F O of the F 1 F O ATP synthase forms a voltage-sensitive channel, the persistent opening of which leads to rapid and uncontrolled depolarization of the IMM in cells. Prolonged high matrix Ca 2+ enlarges the c-subunit ring and unhooks it from cyclophilin D/cyclosporine A binding sites in the ATP synthase F 1 , providing a mechanism for mPTP opening. In contrast, recombinant F 1 beta-subunit applied exogenously to the purified c-subunit enhances the probability of pore closure. Depletion of the c-subunit attenuates Ca 2+ -induced IMM depolarization and inhibits Ca 2+ and reactive oxygen species-induced cell death whereas increasing the expression or single-channel conductance of the c-subunit sensitizes to death. We conclude that a highly regulated c-subunit leak channel is a candidate for the mPTP. Beyond cell death, these findings also imply that increasing the probability of c-subunit channel closure in a healthy cell will enhance IMM coupling and increase cellular metabolic efficiency.metabolism | necrosis | apoptosis | ion channel | excitotoxicity M itochondria produce ATP by oxidative phosphorylation (OXPHOS). Leak currents in the inner mitochondrial membrane (IMM) reduce the efficiency of this process by uncoupling the electron transport system from ATP synthase activity. Many studies have described the biophysical and pharmacological features of an IMM pore [the mitochondrial permeability transition pore (mPTP)] that is responsible for a rapid IMM uncoupling, causing osmotic shifts within the mitochondrial matrix in the setting of cellular Ca 2+ dysregulation and adenine nucleotide depletion (1-4). Some studies suggest that such uncoupling also functions during physiological events and that the mPTP may transiently operate as a Ca 2+ -release channel (5-7). Although models for the molecular identity of the mPTP have been proposed (8), deletions of putative components, such as adenine nucleotide translocase (ANT) and the voltagedependent anion channel (VDAC), have failed to prevent rapid depolarizations (9). In the meantime, nonpore forming regulatory components of the mPTP, such as cyclophilin D (CypD), have been extensively investigated (10, 11).We recently reported a leak conductance sensitive to ATP/ ADP and the Bcl-2 family member B-cell lymphoma-extra large (Bcl-x L ) within the membrane of isolated submitochondrial vesicles (SMVs) enriched in ATP synthase (12, 13). We demonstrated binding of Bcl-x L within F 1 to the beta-subunit of the ATP synthase, suggesting that the channel responsible for the leak conductance lies within the memb...

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“…1B). In previous supportive reports, Bonora et al and Giorgio et al also made a strong case for the pore residing somewhere within the F 1 F O ATP synthase (19,20). This concept was first proposed in 2009 due to the ability of the F 1 F O ATP synthase to bind with CypD (21).…”

mentioning

confidence: 97%

“…This concept was first proposed in 2009 due to the ability of the F 1 F O ATP synthase to bind with CypD (21). Recently, it was shown that gene silencing of isomers of the c-subunit of the ATP synthase inhibited MPTP opening (19). In addition, CypD was shown to bind to oligomycin sensitivity-conferring protein (OSCP), the oligomycin-sensitive component of the F 1 F O ATP synthase, which triggers MPTP opening through dimerization of the F 1 F O ATP synthase (20).…”

mentioning

confidence: 99%

Identifying the components of the elusive mitochondrial permeability transition pore

Karch

Molkentin

2014

Proc. Natl. Acad. Sci. U.S.A.

113

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Role of the c subunit of the F_OATP synthase in mitochondrial permeability transition

Cited by 425 publications

References 75 publications

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

An uncoupling channel within the c-subunit ring of the F ₁ F _O ATP synthase is the mitochondrial permeability transition pore

Identifying the components of the elusive mitochondrial permeability transition pore

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Role of the c subunit of the FOATP synthase in mitochondrial permeability transition

Cited by 425 publications

References 75 publications

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

An uncoupling channel within the c-subunit ring of the F 1 F O ATP synthase is the mitochondrial permeability transition pore

Identifying the components of the elusive mitochondrial permeability transition pore

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Role of the c subunit of the F_OATP synthase in mitochondrial permeability transition

An uncoupling channel within the c-subunit ring of the F ₁ F _O ATP synthase is the mitochondrial permeability transition pore