Special Issue "Mitochondrial Permeability Transition"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Organelle Function".

Deadline for manuscript submissions: closed (30 November 2020).

Special Issue Editors

Prof. Dr. Paolo Bernardi
E-Mail Website1 Website2
Guest Editor
Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, I-35131 Padova, Italy
Interests: mitochondria; calcium; channels; permeability transition; ATP synthase; cell death
Special Issues, Collections and Topics in MDPI journals
Dr. Evgeny V. Pavlov
E-Mail Website
Co-Guest Editor
College of Dentistry, Department of Molecular Pathobiology, New York University, New York, NY, USA
Interests: role of mitochondria in cell death; permeability transition pore; inorganic polyphosphate in mammalian cells; calcium signaling; energy metabolism

Special Issue Information

Dear Colleagues,

For mitochondria to fulfill their bioenergetic function, mitochondrial inner membrane permeability needs to be tightly regulated. According to the fourth postulate of the chemiosmotic hypothesis, the inner membrane is a “specialised coupling membrane which has a low permeability to protons and to anions and cations generally” (Mitchell, P. Chemiosmotic coupling in oxidative and photosynthetic phosphorylation, Glynn Research, Bodmin Cornwall, England 1966, reprinted in Biochim Biophys Acta 2011, 1807, 1507-1538). This allows harnessing of the proton gradient through ATP synthase, completing the final step of oxidative phosphorylation. The mitochondrial permeability transition (mPT) is a reversible permeability increase of the inner membrane that can be triggered by matrix Ca2+. Initially considered an in vitro artifact, today the mPT is considered to be a regulated process mediated by opening of a high-conductance channel, the permeability transition pore (PTP). The PTP is currently investigated both as a physiological process involved in modulation of mitochondrial function and as a central event leading to disruption of cellular energy metabolism and cell death. As a pathological event, the mPT has been implicated as a central cause of cell damage in many conditions, including stroke, heart ischemia-reperfusion injury, muscular dystrophies and neurodegenerative diseases. Recent breakthrough discoveries have been made that significantly advance our understanding of the mPT. At the same time, these discoveries led to increasing appreciation of the tremendous complexity of the mPT, to the generation of new exciting theories and to new challenges, which are the matter of a lively debate. This Special Issue will focus on current progress in understanding the molecular mechanisms and pathophysiological role of this multifaceted phenomenon. We hope that it will serve as a platform for the exchange of new ideas and that it will further stimulate the development of the field.

Prof. Paolo Bernardi
Dr. Evgeny V. Pavlov
Guest Editors

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Keywords

  • calcium
  • ROS
  • permeability transition pore
  • ATP synthase
  • adenine nucleotide translocator
  • cyclophilin D

Published Papers (8 papers)

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Research

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Article
Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS
Cells 2021, 10(2), 320; https://doi.org/10.3390/cells10020320 - 04 Feb 2021
Viewed by 1046
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration. There are no cures or effective treatments for ALS. Therapeutic hypothermia is effectively used clinically to mitigate mortality in patients with acute acquired brain injury and in surgical settings [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration. There are no cures or effective treatments for ALS. Therapeutic hypothermia is effectively used clinically to mitigate mortality in patients with acute acquired brain injury and in surgical settings to minimize secondary brain injury. The efficacy of therapeutic hypothermia in chronic neurodegenerative disorders has not been examined. We tested the hypothesis that mild hypothermia/cold acclimation is therapeutic in a transgenic mouse model of ALS caused by expression of mutated human superoxide dismutase-1 gene. At presymptomatic stages of disease, body temperatures (oral and axial) of mutant male mice were persistently hyperthermic (38–38.5 °C) compared to littermate controls, but at end-stage disease mice were generally hypothermic (36–36.5 °C). Presymptomatic mutant mice (awake-freely moving) were acclimated to systemic mild hypothermia using an environmentally controlled chamber (12 h-on/12-off or 24 h-on/24 h-off) to lower body temperature (1–3 °C). Cooled ALS mice showed a significant delay in disease onset (103–112 days) compared to normothermia mice (80–90 days) and exhibited significant attenuation of functional decline in motor performance. Cooled mice examined at 80 days had reduced motor neuron loss, mitochondrial swelling, and spinal cord inflammation compared to non-cooled mice. Cooling attenuated the loss of heat-shock protein 70, mitochondrial uncoupling protein-3, and sumoylated-1 (SUMO1)-conjugated proteins in skeletal muscle and disengaged the mitochondrial permeability transition pore. Cooled ALS mice had a significant extension of lifespan (148 ± 7 days) compared to normothermic mice (135 ± 4 days). Thus, intermittent systemic mild hypothermia is therapeutic in mouse ALS with protective effects manifested within the CNS and skeletal muscle that target mitochondria. Full article
(This article belongs to the Special Issue Mitochondrial Permeability Transition)
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Article
Genetic Approach to Elucidate the Role of Cyclophilin D in Traumatic Brain Injury Pathology
Cells 2021, 10(2), 199; https://doi.org/10.3390/cells10020199 - 20 Jan 2021
Viewed by 836
Abstract
Cyclophilin D (CypD) has been shown to play a critical role in mitochondrial permeability transition pore (mPTP) opening and the subsequent cell death cascade. Studies consistently demonstrate that mitochondrial dysfunction, including mitochondrial calcium overload and mPTP opening, is essential to the pathobiology of [...] Read more.
Cyclophilin D (CypD) has been shown to play a critical role in mitochondrial permeability transition pore (mPTP) opening and the subsequent cell death cascade. Studies consistently demonstrate that mitochondrial dysfunction, including mitochondrial calcium overload and mPTP opening, is essential to the pathobiology of cell death after a traumatic brain injury (TBI). CypD inhibitors, such as cyclosporin A (CsA) or NIM811, administered following TBI, are neuroprotective and quell neurological deficits. However, some pharmacological inhibitors of CypD have multiple biological targets and, as such, do not directly implicate a role for CypD in arbitrating cell death after TBI. Here, we reviewed the current understanding of the role CypD plays in TBI pathobiology. Further, we directly assessed the role of CypD in mediating cell death following TBI by utilizing mice lacking the CypD encoding gene Ppif. Following controlled cortical impact (CCI), the genetic knockout of CypD protected acute mitochondrial bioenergetics at 6 h post-injury and reduced subacute cortical tissue and hippocampal cell loss at 18 d post-injury. The administration of CsA following experimental TBI in Ppif-/- mice improved cortical tissue sparing, highlighting the multiple cellular targets of CsA in the mitigation of TBI pathology. The loss of CypD appeared to desensitize the mitochondrial response to calcium burden induced by TBI; this maintenance of mitochondrial function underlies the observed neuroprotective effect of the CypD knockout. These studies highlight the importance of maintaining mitochondrial homeostasis after injury and validate CypD as a therapeutic target for TBI. Further, these results solidify the beneficial effects of CsA treatment following TBI. Full article
(This article belongs to the Special Issue Mitochondrial Permeability Transition)
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Article
The Effects of PK11195 and Protoporphyrin IX Can Modulate Chronic Alcohol Intoxication in Rat Liver Mitochondria under the Opening of the Mitochondrial Permeability Transition Pore
Cells 2020, 9(8), 1774; https://doi.org/10.3390/cells9081774 - 24 Jul 2020
Cited by 2 | Viewed by 841
Abstract
Decades of active research have shown that mitochondrial dysfunction, the associated oxidative stress, impaired anti-stress defense mechanisms, and the activation of the proapoptotic signaling pathways underlie pathological changes in organs and tissues. Pathologies caused by alcohol primarily affect the liver. Alcohol abuse is [...] Read more.
Decades of active research have shown that mitochondrial dysfunction, the associated oxidative stress, impaired anti-stress defense mechanisms, and the activation of the proapoptotic signaling pathways underlie pathological changes in organs and tissues. Pathologies caused by alcohol primarily affect the liver. Alcohol abuse is the cause of many liver diseases, such as steatosis, alcoholic steatohepatitis, fibrosis, cirrhosis, and, potentially, hepatocellular cancer. In this study, the effect of chronic alcohol exposure on rat liver mitochondria was investigated. We observed an ethanol-induced increase in sensitivity to calcium, changes in the level of protein kinase Akt and GSK-3β phosphorylation, an induction of the mitochondrial permeability transition pore (mPTP), and strong alterations in the expression of mPTP regulators. Moreover, we also showed an enhanced effect of PK11195 and PPIX, on the parameters of the mPTP opening in rat liver mitochondria (RLM) isolated from ethanol-treated rats compared to the RLM from control rats. We suggest that the results of this study could help elucidate the mechanisms of chronic ethanol action on the mitochondria and contribute to the development of new therapeutic strategies for treating the effects of ethanol-related diseases. Full article
(This article belongs to the Special Issue Mitochondrial Permeability Transition)
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Review

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Review
Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer’s Disease
by and
Cells 2021, 10(3), 649; https://doi.org/10.3390/cells10030649 - 15 Mar 2021
Cited by 2 | Viewed by 781
Abstract
Advanced age is the greatest risk factor for aging-related brain disorders including Alzheimer’s disease (AD). However, the detailed mechanisms that mechanistically link aging and AD remain elusive. In recent years, a mitochondrial hypothesis of brain aging and AD has been accentuated. Mitochondrial permeability [...] Read more.
Advanced age is the greatest risk factor for aging-related brain disorders including Alzheimer’s disease (AD). However, the detailed mechanisms that mechanistically link aging and AD remain elusive. In recent years, a mitochondrial hypothesis of brain aging and AD has been accentuated. Mitochondrial permeability transition pore (mPTP) is a mitochondrial response to intramitochondrial and intracellular stresses. mPTP overactivation has been implicated in mitochondrial dysfunction in aging and AD brains. This review summarizes the up-to-date progress in the study of mPTP in aging and AD and attempts to establish a link between brain aging and AD from a perspective of mPTP-mediated mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Mitochondrial Permeability Transition)
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Review
Mitochondrial Dysfunction and Permeability Transition in Neonatal Brain and Lung Injuries
Cells 2021, 10(3), 569; https://doi.org/10.3390/cells10030569 - 05 Mar 2021
Viewed by 703
Abstract
This review discusses the potential mechanistic role of abnormally elevated mitochondrial proton leak and mitochondrial bioenergetic dysfunction in the pathogenesis of neonatal brain and lung injuries associated with premature birth. Providing supporting evidence, we hypothesized that mitochondrial dysfunction contributes to postnatal alveolar developmental [...] Read more.
This review discusses the potential mechanistic role of abnormally elevated mitochondrial proton leak and mitochondrial bioenergetic dysfunction in the pathogenesis of neonatal brain and lung injuries associated with premature birth. Providing supporting evidence, we hypothesized that mitochondrial dysfunction contributes to postnatal alveolar developmental arrest in bronchopulmonary dysplasia (BPD) and cerebral myelination failure in diffuse white matter injury (WMI). This review also analyzes data on mitochondrial dysfunction triggered by activation of mitochondrial permeability transition pore(s) (mPTP) during the evolution of perinatal hypoxic-ischemic encephalopathy. While the still cryptic molecular identity of mPTP continues to be a subject for extensive basic science research efforts, the translational significance of mitochondrial proton leak received less scientific attention, especially in diseases of the developing organs. This review is focused on the potential mechanistic relevance of mPTP and mitochondrial dysfunction to neonatal diseases driven by developmental failure of organ maturation or by acute ischemia-reperfusion insult during development. Full article
(This article belongs to the Special Issue Mitochondrial Permeability Transition)
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Review
Mitochondrial Cyclosporine A-Independent Palmitate/Ca2+-Induced Permeability Transition Pore (PA-mPT Pore) and Its Role in Mitochondrial Function and Protection against Calcium Overload and Glutamate Toxicity
Cells 2021, 10(1), 125; https://doi.org/10.3390/cells10010125 - 11 Jan 2021
Viewed by 670
Abstract
A sharp increase in the permeability of the mitochondrial inner membrane known as mitochondrial permeability transition (or mPT) occurs in mitochondria under the conditions of Ca2+ and ROS stress. Permeability transition can proceed through several mechanisms. The most common mechanism of mPT [...] Read more.
A sharp increase in the permeability of the mitochondrial inner membrane known as mitochondrial permeability transition (or mPT) occurs in mitochondria under the conditions of Ca2+ and ROS stress. Permeability transition can proceed through several mechanisms. The most common mechanism of mPT is based on the opening of a cyclosporine A (CSA)-sensitive protein channel in the inner membrane. In addition to the CSA-sensitive pathway, mPT can occur through the transient opening of lipid pores, emerging in the process of formation of palmitate/Ca2+ complexes. This pathway is independent of CSA and likely plays a protective role against Ca2+ and ROS toxicity. The review considers molecular mechanisms of formation and regulation of the palmitate/Ca2+-induced pores, which we designate as PA-mPT to distinguish it from the classical CSA-sensitive mPT. In the paper, we discuss conditions of its opening in the biological membranes, as well as its role in the physiological and pathophysiological processes. Additionally, we summarize data that indicate the involvement of PA-mPT in the protection of mitochondria against calcium overload and glutamate-induced degradation in neurons. Full article
(This article belongs to the Special Issue Mitochondrial Permeability Transition)
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Review
The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity
Cells 2021, 10(1), 79; https://doi.org/10.3390/cells10010079 - 06 Jan 2021
Cited by 8 | Viewed by 2244
Abstract
The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+ and NAD+. The [...] Read more.
The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+ and NAD+. The various pathways that control the channel activity, directly or indirectly, can therefore either inhibit or accelerate aging or retard or enhance the progression of aging-driven degenerative diseases and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles, protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. The increased activity of mPTP in aging turns autophagy/mitophagy into a destructive process leading to cell aging and death. Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP. Therefore, elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease. Full article
(This article belongs to the Special Issue Mitochondrial Permeability Transition)
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Review
The Role of Adenine Nucleotide Translocase in the Mitochondrial Permeability Transition
Cells 2020, 9(12), 2686; https://doi.org/10.3390/cells9122686 - 15 Dec 2020
Cited by 4 | Viewed by 660
Abstract
The mitochondrial permeability transition, a Ca2+-induced significant increase in permeability of the inner mitochondrial membrane, plays an important role in various pathologies. The mitochondrial permeability transition is caused by induction of the permeability transition pore (PTP). Despite significant effort, the molecular [...] Read more.
The mitochondrial permeability transition, a Ca2+-induced significant increase in permeability of the inner mitochondrial membrane, plays an important role in various pathologies. The mitochondrial permeability transition is caused by induction of the permeability transition pore (PTP). Despite significant effort, the molecular composition of the PTP is not completely clear and remains an area of hot debate. The Ca2+-modified adenine nucleotide translocase (ANT) and F0F1 ATP synthase are the major contenders for the role of pore in the PTP. This paper briefly overviews experimental results focusing on the role of ANT in the mitochondrial permeability transition and proposes that multiple molecular entities might be responsible for the conductance pathway of the PTP. Consequently, the term PTP cannot be applied to a single specific protein such as ANT or a protein complex such as F0F1 ATP synthase, but rather should comprise a variety of potential contributors to increased permeability of the inner mitochondrial membrane. Full article
(This article belongs to the Special Issue Mitochondrial Permeability Transition)
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