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

Background: Hypertension is one of the most common risk factors for atrial fibrillation (AF), although the precise cellular and molecular mechanism(s) by which hypertension leads to AF are not well understood. Isolevuglandins (IsoLGs) are highly reactive dicarbonyl products of lipid peroxidation responsible for a major component of oxidative stress-related injury. In a mouse model of hypertension, we recently demonstrated that IsoLGs are elevated in hypertensive mouse atria and that an IsoLG scavenger reduced both IsoLG burden and AF susceptibility. Hypothesis: In this study, we hypothesized that IsoLGs can promote AF by inducing proarrhythmic metabolic and electrophysiologic (EP) changes in atrial cardiomyocytes. Methods and Results: Using standard patch clamp methods, we found significant changes in action potential properties of isolated mouse atrial cardiomyocytes exposed to IsoLGs (1μM, n=15 cells), including elevation of resting membrane potential, shortening of APD and reduction of V max . Acute IsoLG treatment led to a reduction of intracellular ATP production in atrial HL-1 cardiomyocytes, as measured by using a luminescence assay. Employing TMRM and Mitotracker Green staining for confocal and high-throughput screening (HTS) live-cell imaging assays, we also found that IsoLGs decreased mitochondrial membrane potential (compared to control, TMRM fluorescence decreased by 23%, 28%, 36% and 42%, respectively, when exposed to 0.01, 0.1, 0.5 and 1μM concentrations of IsoLG) accompanied by increased apoptosis (Cell Event Caspase-3/7 Green Detection Reagent) in a concentration-dependent manner, suggesting a prolonged mitochondrial transition pore opening. Moreover, cell metabolism assays performed using Agilent’s Seahorse XF96 extracellular flux analyzer revealed that IsoLGs exert a concentration dependent decrease in basal oxygen consumption rate and ATP production in HL-1 atrial cardiomyocytes. Conclusion: Together, these findings indicate that IsoLGs promote proarrhythmic EP and mitochondrial effects in atrial cells and thus may provide a novel therapeutic target for AF.

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Novel mitochondrial transition pore inhibitor N ‐methyl‐4‐isoleucine cyclosporin is a new therapeutic option in acute pancreatitis

The Journal of Physiology ◽

10.1113/jp278517 ◽

2019 ◽

Vol 597 (24) ◽

pp. 5879-5898 ◽

Cited By ~ 6

Author(s):

Emese Tóth ◽

József Maléth ◽

Noémi Závogyán ◽

Júlia Fanczal ◽

Anna Grassalkovich ◽

...

Keyword(s):

Acute Pancreatitis ◽

Therapeutic Option ◽

Mitochondrial Transition Pore

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PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning

Cardiovascular Research ◽

10.1016/j.cardiores.2005.07.014 ◽

2006 ◽

Vol 69 (1) ◽

pp. 178-185 ◽

Cited By ~ 148

Author(s):

J BOPASSA ◽

R FERRERA ◽

O GATEAUROESCH ◽

E COUTURELEPETIT ◽

M OVIZE

Keyword(s):

Mitochondrial Transition Pore ◽

Controlled Reperfusion

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Does Declining Mitochondrial NAD+ and Unscheduled Opening of Mitochondrial Transition Pore Promote Mammalian Aging?

Blood ◽

10.1182/blood.v116.21.sci-3.sci-3 ◽

2010 ◽

Vol 116 (21) ◽

pp. SCI-3-SCI-3

Author(s):

David Sinclair ◽

Angela V. Hafner ◽

Ana Gomes ◽

Jing Liang ◽

Yana Cen ◽

...

Keyword(s):

Board Of Directors ◽

Memory Deficits ◽

Dependent Manner ◽

Advisory Committees ◽

Model Of Alzheimer’S Disease ◽

Age Related ◽

Promote Cell Survival ◽

Mitochondrial Defects ◽

Equity Ownership ◽

Mitochondrial Transition Pore

Abstract Abstract SCI-3 The processes that lead to the susceptibility of post-mitotic tissues to diseases of aging are poorly understood, but mitochondria are considered a key regulator. SIRT3 is mitochondrial sirtuin, a member a family of NAD+-dependent deacetylases. We have previously shown that increased levels of NAD+ in mitochondria promote cell survival in a SIRT3-dependent manner, but how this protection is mediated is unknown. Here we show that mitochondrial NAD+ levels decline dramatically with age and that SIRT3 is a critical component and regulator of the mitochondrial transition pore (MTP). Mice lacking SIRT3 exhibit hyperacetylation of the MTP with age, and as a result, develop multiple defects in post-mitotic tissues as they age, including mitochondrial defects, susceptibility to cardiac failure, and learning and memory deficits. In a mouse model of Alzheimer's disease (AD), SIRT3 knockout mice show striking phenotypes including small size, kyphosis, and a markedly reduced lifespan. Similar to mice, human brain samples show that acetylation of the MTP increases with age and with AD. These findings indicate that declining NAD levels with age lead to memory deficits and accelerate age-related diseases in post-mitotic tissues due to a decline in SIRT3 activity and unscheduled opening of the MTP. Disclosures: Sinclair: GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

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Mitochondrial fission and fusion in secondary brain damage after CNS insults

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16671528 ◽

2016 ◽

Vol 36 (12) ◽

pp. 2022-2033 ◽

Cited By ~ 38

Author(s):

Justin Balog ◽

Suresh L Mehta ◽

Raghu Vemuganti

Keyword(s):

Brain Damage ◽

Neuronal Death ◽

Mitochondrial Fission ◽

Chronic Injury ◽

Secondary Brain Damage ◽

Mitochondrial Dynamic ◽

Altered Expression ◽

Calcium Buffering ◽

Mitochondrial Transition Pore ◽

And Function

Mitochondria are dynamically active organelles, regulated through fission and fusion events to continuously redistribute them across axons, dendrites, and synapses of neurons to meet bioenergetics requirements and to control various functions, including cell proliferation, calcium buffering, neurotransmission, oxidative stress, and apoptosis. However, following acute or chronic injury to CNS, altered expression and function of proteins that mediate fission and fusion lead to mitochondrial dynamic imbalance. Particularly, if the fission is abnormally increased through pro-fission mediators such as Drp1, mitochondrial function will be impaired and mitochondria will become susceptible to insertion of proapototic proteins. This leads to the formation of mitochondrial transition pore, which eventually triggers apoptosis. Thus, mitochondrial dysfunction is a major promoter of neuronal death and secondary brain damage after an insult. This review discusses the implications of mitochondrial dynamic imbalance in neuronal death after acute and chronic CNS insults.

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Evidence for a Novel, Caspase-8-Independent, Fas Death Domain-Mediated Apoptotic Pathway

Journal of Biomedicine and Biotechnology ◽

10.1155/s1110724304308041 ◽

2004 ◽

Vol 2004 (1) ◽

pp. 41-51 ◽

Cited By ~ 14

Author(s):

Hanping Feng ◽

Yi Zeng ◽

Michael W. Graner ◽

Luke Whitesell ◽

Emmanuel Katsanis

Keyword(s):

Transmembrane Potential ◽

Caspase 8 ◽

Death Domain ◽

Caspase Inhibitor ◽

Caspase Activation ◽

Null Cell ◽

Apoptotic Pathway ◽

Induced Apoptosis ◽

Mitochondrial Transition Pore ◽

Pore Permeability

Certain caspase-8 null cell lines demonstrate resistance to Fas-induced apoptosis, indicating that the Fas/FasL apoptotic pathway may be caspase-8-dependent. Some reports, however, have shown that Fas induces cell death independent of caspase-8. Here we provide evidence for an alternative, caspase-8-independent, Fas death domain-mediated apoptotic pathway. Murine 12B1-D1 cells express procaspase-3, -8, and -9, which were activated upon the dimerization of Fas death domain. Bid was cleaved and mitochondrial transmembrane potential was disrupted in this apoptotic process. All apoptotic events were completely blocked by the broad-spectrum caspase inhibitor Z-VAD-FMK, but not by other peptide caspase inhibitors. Cyclosporin A (CsA), which inhibits mitochondrial transition pore permeability, blocked neither pore permeability disruption nor caspase activation. However, CsA plus caspase-8 inhibitor blocked all apoptotic events of 12B1-D1 induced by Fas death domain dimerization. Our data therefore suggest that there is a novel, caspase-8-independent, Z-VAD-FMK-inhibitable, apoptotic pathway in 12B1-D1 cells that targets mitochondria directly.

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P437Beta3-adrenergic receptor stimulation reduces ischemia/reperfusion injury through inhibition of the mitochondrial transition pore opening (mPTP) and subsequent apoptotic inhibition

Cardiovascular Research ◽

10.1093/cvr/cvu091.116 ◽

2014 ◽

Vol 103 (suppl 1) ◽

pp. S80.4-S80

Author(s):

J Garcia-Prieto ◽

D Sanz-Rosa ◽

A Pun-Garcia ◽

R Villena-Gutierrez ◽

R Bourio-Martinez ◽

...

Keyword(s):

Reperfusion Injury ◽

Adrenergic Receptor ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Receptor Stimulation ◽

Pore Opening ◽

Mitochondrial Transition Pore

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mtPTP (mitochondrial transition pore)

Encyclopedia of Genetics, Genomics, Proteomics and Informatics ◽

10.1007/978-1-4020-6754-9_10878 ◽

2008 ◽

pp. 1281-1281

Keyword(s):

Mitochondrial Transition Pore

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Modulation of Mitochondrial Transition Pore Components by Thyroid Hormone

Endocrinology ◽

10.1210/en.2004-1161 ◽

2005 ◽

Vol 146 (5) ◽

pp. 2462-2472 ◽

Cited By ~ 18

Author(s):

Einav Yehuda-Shnaidman ◽

Bella Kalderon ◽

Jacob Bar-Tana

Keyword(s):

Thyroid Hormone ◽

Cyclosporin A ◽

Adenine Nucleotide ◽

Jurkat Cells ◽

Gh3 Cells ◽

Metabolic Efficiency ◽

Mitochondrial Depolarization ◽

Voltage Dependent Anion Channel ◽

Bcl2 Family ◽

Mitochondrial Transition Pore

Abstract Thyroid hormone (TH) modulates metabolic efficiency by controlling the coupling of mitochondrial oxidative phosphorylation. However, its uncoupling mode of action is still enigmatic. Treatment of Jurkat or GH3 cells with T3 is reported here to result in limited, Cyclosporin A-sensitive mitochondrial depolarization, conforming to low conductance gating of the mitochondrial transition pore (MTP). MTP protein components induced by T3 treatment were verified in T3-treated and hypothyroid rat liver as well as in Jurkat cells. T3 treatment resulted in increase in mitochondrial Bax and Bak together with decreased mitochondrial Bcl2. T3-induced mitochondrial depolarization was aborted by overexpression of Bcl2. In contrast to Bax-Bcl2 family proteins, some other MTP components were either not induced by T3 (e.g. voltage-dependent anion channel) or were induced, but were not involved in Cyclosporin A-sensitive MTP gating (e.g. Cyclophilin D and adenine nucleotide translocase-2) Hence, TH-induced mitochondrial uncoupling may be ascribed to low conductance MTP gating mediated by TH-induced increase in mitochondrial proapoptotic combined with a decrease in mitochondrial antiapoptotic proteins of the Bax-Bcl2 family.

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