Cell death disguised: The mitochondrial permeability transition pore as the c-subunit of the F1FO ATP synthase

Jonas, Elizabeth A.; Porter, George A.; Beutner, Gisela; Mnatsakanyan, Nelli; Alavian, Kambiz N.

doi:10.1016/j.phrs.2015.04.013

Cited by 71 publications

(35 citation statements)

References 160 publications

(220 reference statements)

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“…Interestingly, DEX has the unique ability to bind mitochondrial F1Fo-ATP synthase and improve mitochondrial efficiency by concomitant increase of ATP synthesis and reduction of O 2 consumption (Alavian et al, 2012;Alavian et al, 2015). Consistent with this, and with recent evidence that F1Fo-ATP synthase participates in the supramolecular complex organization of the mitochondrial transition pore complex (Bonora et al, 2015;Jonas et al, 2015), DEX inhibits depolarizing membrane currents in dysfunctional mitochondria and prevents organelle swelling in conditions predisposing to pore opening (Cassarino et al, 1998;Sayeed et al, 2006). Remarkably, DEX also detoxifies mitochondrial reactive oxygen species and reduces cell death in in vitro models of neurotoxicity (Cassarino et al, 1998;Danzeisen et al, 2006;Ferrari-Toninelli et al, 2010).…”

Section: Introductionsupporting

confidence: 70%

“…In this regard, it is worth noting that drugs such as cyclosporin, which is also able to confer ischaemic neuroprotection by preventing mitochondrial derangement (Uchino et al, 2002), target mechanisms leading to permeability transition pore opening, rather than F1Fo ATP synthase activity. Even though we now know that different subunits of mitochondrial ATP synthase participate in the organization of the permeability transition pore complex (Bernardi et al, 2015;Bonora et al, 2015;Jonas et al, 2015) the mode of action of cyclosporin and DEX are substantially different with respect to the mechanisms operating during ischaemic neurodegeneration. Indeed, whereas a potentiation of mitochondrial ATP production by DEX can prevent almost all of the detrimental events prompted by the ischaemic insults, inhibition of mitochondrial permeability transition by cyclosporin is typically downstream from both energy failure and early necrotic or apoptotic signalling within the neurovascular unit.…”

Section: Discussionmentioning

confidence: 99%

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Dexpramipexole improves bioenergetics and outcome in experimental stroke

Muzzi

Gerace

Buonvicino

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEDexpramipexole, a drug recently tested in patients with amyotrophic lateral sclerosis (ALS,) is able to bind F1Fo ATP synthase and increase mitochondrial ATP production. Here, we have investigated its effects on experimental ischaemic brain injury. EXPERIMENTAL APPROACHThe effects of dexpramipexole on bioenergetics, Ca 2+ fluxes, electrophysiological functions and death were evaluated in primary neural cultures and hippocampal slices exposed to oxygen-glucose deprivation (OGD). Effects on infarct volumes and neurological functions were also evaluated in mice following proximal or distal middle cerebral artery occlusion (MCAo). Distribution of dexpramipexole within the ischaemic brain was evaluated by means of mass spectrometry imaging. KEY RESULTSDexpramipexole increased mitochondrial ATP production in cultured neurons or glia and reduces energy failure, prevents intracellular Ca 2+ overload and affords cytoprotection when cultures are exposed to OGD. This compound also counteracted ATP depletion, mitochondrial swelling, anoxic depolarization, loss of synaptic activity and neuronal death in hippocampal slices subjected to OGD. Post-ischaemic treatment with dexpramipexole, at doses consistent with those already used in ALS patients, reduced brain infarct size and ameliorated neuroscore in mice subjected to transient or permanent MCAo. Notably, the concentrations of dexpramipexole reached within the ischaemic penumbra equalled those found neuroprotective in vitro. CONCLUSION AND IMPLICATIONSDexpramipexole, a compound able to increase mitochondrial F1Fo ATP-synthase activity reduced ischaemic brain injury. These findings, together with the excellent brain penetration and favourable safety profile in humans, make dexpramipexole a drug with realistic translational potential for the treatment of stroke.

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Section: Introductionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Dexpramipexole improves bioenergetics and outcome in experimental stroke

Muzzi

Gerace

Buonvicino

et al. 2017

British J Pharmacology

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“…3,8,9 Moreover, genetic manipulations of the C-subunit of ATP synthase correlate with alterations in mPTP activity. 6 This suggests that the C-subunit of the ATP synthase is an essential component of the mPTP channel.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial permeability transition pore induction is linked to formation of the complex of ATPase C-subunit, polyhydroxybutyrate and inorganic polyphosphate

Elustondo

Nichols

Negoda

et al. 2016

Cell Death Discovery

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Mitochondrial permeability transition pore (mPTP) opening allows free movement of ions and small molecules leading to mitochondrial membrane depolarization and ATP depletion that triggers cell death. A multi-protein complex of the mitochondrial ATP synthase has an essential role in mPTP. However, the molecular identity of the central 'pore' part of mPTP complex is not known. A highly purified fraction of mammalian mitochondria containing C-subunit of ATPase (C-subunit), calcium, inorganic polyphosphate (polyP) and polyhydroxybutyrate (PHB) forms ion channels with properties that resemble the native mPTP. We demonstrate here that amount of this channel-forming complex dramatically increases in intact mitochondria during mPTP activation. This increase is inhibited by both Cyclosporine A, an inhibitor of mPTP and Ruthenium Red, an inhibitor of the Mitochondrial Calcium Uniporter. Similar increases in the amount of complex formation occurs in areas of mouse brain damaged by ischemia-reperfusion injury. These findings suggest that calcium-induced mPTP is associated with de novo assembly of a channel comprising C-subunit, polyP and PHB.

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“…ATP synthase has recently been identified as likely to be the elusive main component of the mitochondrial permeability transition pore (MPTP) (233)(234)(235)(236)(237)(238)(239) that is an upstream initiator of programmed cell death (234). One of the proposals is that the centre of the c-subunit ring of the F0 membrane component forms the pore (233). Cancer cells would need to reduce or eliminate ATP synthase from the mitochondria, so that the deregulated state of the mitochondria would not trigger programmed cell death via opening of the MPTP, leading to a need for cancer cells to produce ATP by alternative means.…”

Section: Discussionmentioning

confidence: 99%

Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components

et al. 2015

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-The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti-bacterial properties. The structure of HAMLETlike compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified.

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Cell death disguised: The mitochondrial permeability transition pore as the c-subunit of the F1FO ATP synthase

Cited by 71 publications

References 160 publications

Dexpramipexole improves bioenergetics and outcome in experimental stroke

Dexpramipexole improves bioenergetics and outcome in experimental stroke

Mitochondrial permeability transition pore induction is linked to formation of the complex of ATPase C-subunit, polyhydroxybutyrate and inorganic polyphosphate

Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components

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