Mitochondrial permeability transition triggers the release of mtDNA fragments

Патрушев, М. В.; Kasymov, Vitaliy; Патрушева, В. Е.; Ushakova, Tatjana E.; Gogvadze, Vladimir; Gaziev, A.I.

doi:10.1007/s00018-004-4424-1

Cited by 122 publications

(77 citation statements)

References 45 publications

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“…As neuronal membrane integrity is preserved, the question arises of how mtDNA and Cyt c, coming from the mitochondrial matrix or the intermembrane space, respectively, can exit the cell. Several pieces of evidence indicate that mitochondria are central sensors for axonal degenerative stimuli (62), and the release of mtDNA fragments from PTP in isolated mitochondria has been documented (63). Here, the mitochondrial PTP was found to be involved in the exit of both mtDNA and Cyt c from mitochondria, with a significant reduction in the presence of the PTP desensitizing molecule cyclosporin A.…”

Section: Discussionmentioning

confidence: 82%

Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells

Duregotti

Negro

Scorzeto

et al. 2015

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

104

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An acute and highly reproducible motor axon terminal degeneration followed by complete regeneration is induced by some animal presynaptic neurotoxins, representing an appropriate and controlled system to dissect the molecular mechanisms underlying degeneration and regeneration of peripheral nerve terminals. We have previously shown that nerve terminals exposed to spider or snake presynaptic neurotoxins degenerate as a result of calcium overload and mitochondrial failure. Here we show that toxin-treated primary neurons release signaling molecules derived from mitochondria: hydrogen peroxide, mitochondrial DNA, and cytochrome c. These molecules activate isolated primary Schwann cells, Schwann cells cocultured with neurons and at neuromuscular junction in vivo through the MAPK pathway. We propose that this inter-and intracellular signaling is involved in triggering the regeneration of peripheral nerve terminals affected by other forms of neurodegenerative diseases.motor axon degeneration | presynaptic neurotoxins | mitochondrial alarmins | Schwann cells

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Section: Discussionmentioning

confidence: 82%

Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells

Duregotti

Negro

Scorzeto

et al. 2015

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

104

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“…The translocation of mtDNA from mitochondria to the cytosol was reported in Patrushev et al (118). The mechanism of mtDNA release includes induction of mitochondrial permeability transition pore as cyclosporine A, a potent inhibitor of pore opening, inhibits translocation of mtDNA from mitochondria to the cytosol (70,107,118,119).…”

Section: Fig 3 Released Mtdna Activates Tlr9 and Inflammasome (A)mentioning

confidence: 89%

“…The mechanism of mtDNA release includes induction of mitochondrial permeability transition pore as cyclosporine A, a potent inhibitor of pore opening, inhibits translocation of mtDNA from mitochondria to the cytosol (70,107,118,119). The release of nucleic acids into the extracellular space has been thought to be related to the cell death, including apoptosis and necrosis (139).…”

Section: Fig 3 Released Mtdna Activates Tlr9 and Inflammasome (A)mentioning

confidence: 99%

The Roles of Mitochondrial Damage-Associated Molecular Patterns in Diseases

Nakahira

Shu

Choi

2015

Antioxidants & Redox Signaling

237

164

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“…This idea is consistent with several observations: (i) ion-conducting properties of the mitochondrial polyP/Ca 2ϩ /PHB channel mimic properties of PT pore seen by patch-clamp of native membranes and in experiments on intact mitochondria (see discussion in ref. 6; (ii) polyP/Ca 2ϩ /PHB complex formation requires elevated concentrations of Ca 2ϩ (22), a condition characteristic of Ca 2ϩ -induced PT; (iii) PT development is favored by several membrane proteins (7), as is formation of polyP/Ca 2ϩ /PHB channels in bacteria (23); (iv) both PT in mitochondria and polyP/Ca 2ϩ /PHB complex formation in bacteria are associated with passage of DNA across membranes (24,25); and finally, (v) our inability to detect PT in polyP-deficient cells, even under strong Ca 2ϩ overload, suggests that polyP probably plays a direct, rather than a regulatory, role.…”

Section: Involvement Of Polyp In Regulation Of Normal Mitochondrial Fmentioning

confidence: 99%

Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death

Abramov

Fraley

Diao

et al. 2007

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

191

170

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Polyphosphate (polyP) consists of tens to hundreds of phosphates, linked by ATP-like high-energy bonds. Although polyP is present in mammalian mitochondria, its physiological roles there are obscure. Here, we examine the involvement of polyP in mitochondrial energy metabolism and ion transport. We constructed a vector to express a mitochondrially targeted polyphosphatase, along with a GFP fluorescent tag. Specific reduction of mitochondrial polyP, by polyphosphatase expression, significantly modulates mitochondrial bioenergetics, as indicated by the reduction of inner membrane potential and increased NADH levels. Furthermore, reduction of polyP levels increases mitochondrial capacity to accumulate calcium and reduces the likelihood of the calcium-induced mitochondrial permeability transition, a central event in many types of necrotic cell death. This confers protection against cell death, including that induced by ␤-amyloid peptide, a pathogenic agent in Alzheimer's disease. These results demonstrate a crucial role played by polyP in mitochondrial function of mammalian cells. mitochondria ͉ permeability transition ͉ polyphosphate ͉ ␤-amyloid peptide ͉ necrosis T he chemical and physical properties of polyphosphate (polyP), including its high negative charge and its ability to form complexes with Ca 2ϩ and to form high energy bonds, underlie its potential to play an important role in cell metabolism. Significant amounts of polyP have been found in bacteria and in lower eukaryotes. In those organisms, it provides energy storage and a reserve pool of inorganic phosphate, participates in regulation of gene expression, protects cells from the toxicity of heavy metals by forming complexes with them, and participates in channel formation through assembly into complexes with Ca 2ϩ and polyhydroxybutyrate (PHB) (polyP/Ca 2ϩ /PHB complex) (1, 2) and possibly through interaction with channelforming proteins (3).PolyP has also been found in all higher eukaryotic organisms tested, where it is localized in various subcellular compartments, including mitochondria (4). Furthermore, mitochondrial polyP can form polyP/Ca 2ϩ /PHB complexes (5) with ion-conducting properties similar to those of native mitochondrial permeability transition pore (mPTP) (6). mPTP opening or formation in the mitochondrial inner membrane is believed to underlie the Ca 2ϩ -induced permeability transition (PT), a phenomenon that causes inner membrane depolarization and disruption of ATP synthesis and plays a central role during various types of necrotic and apoptotic cell death (7). The molecular composition of the conducting pathway of mPTP is currently not well defined.Recently, we have raised the possibility that, in vivo, the polyP/ Ca 2ϩ /PHB complex might comprise the ion-conducting part of the mPTP complex (6). If so, mitochondrial polyP should be essential for mPTP opening/formation. Here, we examine the involvement of polyP in normal mitochondrial function and in PT development during stress. To this end, we specifically reduced levels of mitocho...

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Mitochondrial permeability transition triggers the release of mtDNA fragments

Cited by 122 publications

References 45 publications

Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells

Mitochondrial alarmins released by degenerating motor axon terminals activate perisynaptic Schwann cells

The Roles of Mitochondrial Damage-Associated Molecular Patterns in Diseases

Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death

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