The Ca2+-induced membrane transition in mitochondria

Hunter, Douglas R.; Haworth, Robert A.

doi:10.1016/0003-9861(79)90373-4

Cited by 486 publications

(280 citation statements)

References 26 publications

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“…The mitochondrial permeability transition has been characterized by the pioneering work of Hunter and Haworth and corresponds to the sudden increase in the permeability of the inner mitochondrial membrane to molecules of molecular mass up to 1,500 Da (Haworth & Hunter, 1979; Hunter & Haworth, 1979a, 1979b). The opening is due to a nonspecific pore called the mitochondrial permeability transition pore (mPTP) occurring when mitochondria become overloaded with calcium.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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SummaryThe cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.

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Section: Introductionmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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“…In vitro at least, the PT is accompanied by swelling of mitochondria, which has long been known to prevent ATP synthesis (3). The idea that swelling could be mediated by a Ca 2+ -regulated pore was advanced in the 1970s (4,5), and its basic regulatory features were defined in a series of seminal studies in 1979 (6)(7)(8). The PT is mediated by opening of a high-conductance channel, the PT pore (PTP), which was identified by patch-clamping of the inner membrane and called mitochondrial megachannel (MMC) (9)(10)(11)(12).…”

mentioning

confidence: 99%

Dimers of mitochondrial ATP synthase form the permeability transition pore

Giorgio

Stockum

Antoniel³

et al. 2013

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

835

882

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Here we define the molecular nature of the mitochondrial permeability transition pore (PTP), a key effector of cell death. The PTP is regulated by matrix cyclophilin D (CyPD), which also binds the lateral stalk of the F O F 1 ATP synthase. We show that CyPD binds the oligomycin sensitivity-conferring protein subunit of the enzyme at the same site as the ATP synthase inhibitor benzodiazepine 423 (Bz-423), that Bz-423 sensitizes the PTP to Ca 2+ like CyPD itself, and that decreasing oligomycin sensitivity-conferring protein expression by RNAi increases the sensitivity of the PTP to Ca 2+ . Purified dimers of the ATP synthase, which did not contain voltage-dependent anion channel or adenine nucleotide translocator, were reconstituted into lipid bilayers. In the presence of Ca 2+ , addition of Bz-423 triggered opening of a channel with currents that were typical of the mitochondrial megachannel, which is the PTP electrophysiological equivalent. Channel openings were inhibited by the ATP synthase inhibitor AMP-PNP (γ-imino ATP, a nonhydrolyzable ATP analog) and Mg 2+ /ADP. These results indicate that the PTP forms from dimers of the ATP synthase.

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“…The MPT is a consequence of the opening of permeability transition (PT) pores in the mitochondrial inner membrane through which solutes less than 1,500 daltons pass (21)(22)(23). As a consequence of PT pore opening, mitochondria uncouple and undergo large amplitude swelling.…”

mentioning

confidence: 99%

Photodynamic Therapy-induced Apoptosis in Epidermoid Carcinoma Cells

Lam¹,

Oleinick²,

Nieminen³

2001

Journal of Biological Chemistry

269

117

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Photodynamic therapy (PDT), a novel and promising cancer treatment that employs a combination of a photosensitizing chemical and visible light, induces apoptosis in human epidermoid carcinoma A431 cells. However, the precise mechanism of PDT-induced apoptosis is not well characterized. To dissect the pathways of PDT-induced apoptosis, we investigated the involvement of mitochondrial damage by examining a second generation photosensitizer, the silicon phthalocyanine 4 (Pc 4). By using laser-scanning confocal microscopy, we found that Pc 4 localized to cytosolic membranes primarily, but not exclusively, in mitochondria. Formation of mitochondrial reactive oxygen species (ROS) was detected within minutes when cells were exposed to Pc 4 and 670 -675 nm light. This was followed by mitochondrial inner membrane permeabilization, depolarization and swelling, cytochrome c release, and apoptotic death. Desferrioxamine prevented mitochondrial ROS production and the events thereafter. Cyclosporin A plus trifluoperazine, blockers of the mitochondrial permeability transition, inhibited mitochondrial inner membrane permeabilization and depolarization without affecting mitochondrial ROS generation. These data indicate that the mitochondrial ROS are critical in initiating mitochondrial inner membrane permeabilization, which leads to mitochondrial swelling, cytochrome c release to the cytosol, and apoptotic death during PDT with Pc 4.

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The Ca2+-induced membrane transition in mitochondria

Cited by 486 publications

References 26 publications

Mitochondria and aging: A role for the mitochondrial transition pore?

Mitochondria and aging: A role for the mitochondrial transition pore?

Dimers of mitochondrial ATP synthase form the permeability transition pore

Photodynamic Therapy-induced Apoptosis in Epidermoid Carcinoma Cells

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