The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology

Bernardi, Paolo; Rasola, Andrea; Forte, Michael; Lippe, Giovanna

doi:10.1152/physrev.00001.2015

Cited by 509 publications

(475 citation statements)

References 672 publications

(589 reference statements)

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“…Among the numerous components that have been proposed, only CypD is recognized as a real regulator of mPTP but it is not a structural pore component. Recent data propose ATP synthase as being the major component of the pore (Bernardi et al., 2015). This hypothesis is a priori counterintuitive as it seems opposite to the primary function of the enzyme, which is to produce energy, and furthermore requires a strict impermeability of the mitochondrial inner membrane.…”

Section: Putative Molecular Components Of Mptp and Agingmentioning

confidence: 99%

“…This is the case for the voltage‐dependent anion channel (VDAC) and the translocator protein (TSPO) in the outer membrane (Baines, Kaiser, Sheiko, Craigen, & Molkentin, 2007; Kokoszka et al., 2004). Recent data propose a role for ATP synthase as the major component of a multiproteic complex (Bernardi, Rasola, Forte, & Lippe, 2015). Currently, a common agreement considers that cyclophilin D (CypD), a soluble protein located within the mitochondrial matrix, is the main partner of the mPTP (Gutiérrez‐Aguilar & Baines, 2015) and that mPTP formation is greatly sensitized by CypD which lowers the calcium threshold required to trigger mPTP opening.…”

Section: Introductionmentioning

confidence: 99%

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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: Putative Molecular Components Of Mptp and Agingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2018

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“…The mPTP is permeable to pro-apoptotic proteins such as cytochrome c [77]. mPTP opening also leads to further depolarization of the mitochondrial membrane potential with a consequent decrease in ATP production, disordered ionic homeostasis and mitochondrial matrix swelling.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Pathophysiology of status epilepticus

Walker¹

2018

Neuroscience Letters

109

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Status epilepticus (SE) is the maximal expression of epilepsy with a high morbidity and mortality. It occurs due to the failure of mechanisms that terminate seizures.Both human and animal data indicate that the longer a seizure lasts, the less likely it is to stop. Recent evidence suggests that there is a critical transition from an ictal to a post-ictal state, associated with a transition from a spatio-temporally desynchronized state to a highly synchronized state, respectively.As SE continues, it becomes progressively resistant to drugs, in particular benzodiazepines due partly to NMDA receptor-dependent internalization of GABA (A) receptors. Moreover, excessive calcium entry into neurons through excessive NMDA receptor activation results in activation of nitric oxide synthase, calpains, and NADPH oxidase. The latter enzyme plays a critical part in the generation of seizuredependent reactive oxygen species. Calcium also accumulates in mitochondria resulting in mitochondrial failure (decreased ATP production), and opening of the mitochondrial permeability transition pore. Together these changes result in status epilepticus-dependent neuronal death via several pathways. Multiple downstream mechanisms including inflammation, break down of the blood-brain barrier, and changes in gene expression can contribute to later pathological processes including chronic epilepsy and cognitive decline.

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“…In order to keep this manuscript focused on neurosteroid production, we are not reviewing the different aspects of MPT regulation 231:1 affected by this conclusion. Implications from this recent understanding of TSPO and advances toward explaining the MPT process have been critically assessed elsewhere (see review Bernardi et al 2015).…”

Section: Tspo Is Not Part Of the Mitochondrial Permeability Transitiomentioning

confidence: 99%

Current status and future perspectives: TSPO in steroid neuroendocrinology

Selvaraj

2016

Journal of Endocrinology

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The mitochondrial translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), has received significant attention both as a diagnostic biomarker and as a therapeutic target for different neuronal disease pathologies. Recently, its functional basis believed to be mediating mitochondrial cholesterol import for steroid hormone production has been refuted by studies examining both in vivo and in vitro genetic Tspo-deficient models. As a result, there now exists a fundamental gap in the understanding of TSPO function in the nervous system, and its putative pharmacology in neurosteroid production. In this review, we discuss several recent findings in steroidogenic cells that are in direct contradiction to previous studies, and necessitate a re-examination of the purported role for TSPO in de novo neurosteroid biosynthesis. We critically examine the pharmacological effects of different TSPObinding drugs with particular focus on studies that measure neurosteroid levels. We highlight the basis of key misconceptions regarding TSPO that continue to pervade the literature, and the need for interpretation with caution to avoid negative impacts. We also summarize the emerging perspectives that point to new directions that need to be investigated for understanding the molecular function of TSPO, only after which the true potential of this therapeutic target in medicine may be realized.

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The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology

Cited by 509 publications

References 672 publications

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

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

Pathophysiology of status epilepticus

Current status and future perspectives: TSPO in steroid neuroendocrinology

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