Enhanced oxidative stress sensitizes the mitochondrial permeability transition pore to opening in heart from Zucker Fa/fa rats with type 2 diabetes

Riojas-Hernández, Adriana; Bernal‐Ramírez, Judith; Rodríguez-Mier, David; Morales-Marroquín, Flor E.; Domínguez-Barragán, Elvia M.; Borja-Villa, Cuauhtémoc; Rivera-Álvarez, Irais; García‐Rivas, Gerardo; Altamirano, Julio; Garcı́a, Noemı́

doi:10.1016/j.lfs.2015.09.018

Cited by 41 publications

(32 citation statements)

References 77 publications

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“…Dai et al ., ). mPTP opening plays a major role in ischemic heart damage (discussed below) and also contributes to other aging‐dependent cardiac diseases (Zulian et al ., ), diabetes (Riojas‐Hernandez et al ., ), and multiple neurodegenerative diseases (Martin, ). A sampling of the evidence for the role of mPTP in aging‐dependent degenerative diseases is listed in Table .…”

Section: Mptp Activation Is Enhanced By Aging and In Aging‐dependent mentioning

confidence: 99%

The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

Rottenberg¹,

2017

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SummaryExcessive production of mitochondrial reactive oxygen species (mROS) is strongly associated with mitochondrial and cellular oxidative damage, aging, and degenerative diseases. However, mROS also induces pathways of protection of mitochondria that slow aging, inhibit cell death, and increase lifespan. Recent studies show that the activation of the mitochondrial permeability transition pore (mPTP), which is triggered by mROS and mitochondrial calcium overloading, is enhanced in aged animals and humans and in aging‐related degenerative diseases. mPTP opening initiates further production and release of mROS that damage both mitochondrial and nuclear DNA, proteins, and phospholipids, and also releases matrix NAD that is hydrolyzed in the intermembrane space, thus contributing to the depletion of cellular NAD that accelerates aging. Oxidative damage to calcium transporters leads to calcium overload and more frequent opening of mPTP. Because aging enhances the opening of the mPTP and mPTP opening accelerates aging, we suggest that mPTP opening drives the progression of aging. Activation of the mPTP is regulated, directly and indirectly, not only by the mitochondrial protection pathways that are induced by mROS, but also by pro‐apoptotic signals that are induced by DNA damage. We suggest that the integration of these contrasting signals by the mPTP largely determines the rate of cell aging and the initiation of cell death, and thus animal lifespan. The suggestion that the control of mPTP activation is critical for the progression of aging can explain the conflicting and confusing evidence regarding the beneficial and deleterious effects of mROS on health and lifespan.

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Section: Mptp Activation Is Enhanced By Aging and In Aging‐dependent mentioning

confidence: 99%

The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

Rottenberg¹,

2017

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“…Although there is different data regarding the metabolic alterations in obese rats and the development of cardiac changes [27][28][29], no clear evidence concerning obesity-related oxidative stress and inflammation in the heart is present. Thus, investigating the interplay between these risk factors with obesity/MetS onset as well as the interactions with CVD is fundamental.…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular Changes Related to Metabolic Syndrome: Evidence in Obese Zucker Rats

Martinelli

Tomassoni

Moruzzi

et al. 2020

IJMS

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Metabolic syndrome (MetS) is a predictor of cardiovascular diseases, commonly associated with oxidative stress and inflammation. However, the pathogenic mechanisms are not yet fully elucidated. The aim of the study is to evaluate the oxidative status and inflammation in the heart of obese Zucker rats (OZRs) and lean Zucker rats (LZRs) at different ages. Morphological and morphometric analyses were performed in the heart. To study the oxidative status, the malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), protein oxidation, and antioxidant enzymes were measured in plasma and heart. To elucidate the inflammatory markers involved, immunohistochemistry and Western blot were performed for cellular adhesion molecules and proinflammatory cytokines. OZRs were characterized by hypertension, hyperlipidemia, hyperglycemia, and insulin resistance. The obesity increased MDA and decreased the activities of superoxide dismutase (SOD) in plasma as well as in the heart, associated with cardiomyocytes hypertrophy. OxyBlot in plasma and in heart showed an increase of oxidativestate proteins in OZRs. Vascular cell adhesion molecule-1, interleukin-6, and tumor necrosis factor-α expressions in OZRs were higher than those of LZRs. However, these processes did not induce apoptosis or necrosis of cardiomyocytes. Thus, MetS induces the lipid peroxidation and decreased antioxidant defense that leads to heart tissue changes and coronary inflammation.

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“…In diabetes-affected cells, including β-cells (25), adipocytes (26), and skeletal muscle cells (27), cyclophilin D (CypD)–mediated mitochondrial permeability transition is involved in the dissipation of the mitochondrial inner membrane electrochemical gradient, reduction of β-cell mass, and development of insulin resistance. In addition, the mPTP is hypersensitive to Ca 2+ in the diabetic rat heart and thereby contributes to cardiac dysfunction (28). Thus, investigation of diabetes-induced mPTP opening in brain mitochondria is highly valuable for the development of new therapeutic interventions for diabetic neurological complications, including cognitive decline.…”

Section: Introductionmentioning

confidence: 99%

F1F0 ATP Synthase–Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline

Yan

et al. 2016

Diabetes

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Mitochondrial abnormalities are well known to cause cognitive decline. However, the underlying molecular basis of mitochondria-associated neuronal and synaptic dysfunction in the diabetic brain remains unclear. Here, using a mitochondrial single-channel patch clamp and cyclophilin D (CypD)-deficient mice (Ppif −/−) with streptozotocin-induced diabetes, we observed an increase in the probability of Ca2+-induced mitochondrial permeability transition pore (mPTP) opening in brain mitochondria of diabetic mice, which was further confirmed by mitochondrial swelling and cytochrome c release induced by Ca2+ overload. Diabetes-induced elevation of CypD triggers enhancement of F1F0 ATP synthase–CypD interaction, which in turn leads to mPTP opening. Indeed, in patients with diabetes, brain cypD protein levels were increased. Notably, blockade of the F1F0 ATP synthase–CypD interaction by CypD ablation protected against diabetes-induced mPTP opening, ATP synthesis deficits, oxidative stress, and mitochondria dysfunction. Furthermore, the absence of CypD alleviated deficits in synaptic plasticity, learning, and memory in diabetic mice. Thus, blockade of ATP synthase interaction with CypD provides a promising new target for therapeutic intervention in diabetic encephalopathy.

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Enhanced oxidative stress sensitizes the mitochondrial permeability transition pore to opening in heart from Zucker Fa/fa rats with type 2 diabetes

Cited by 41 publications

References 77 publications

The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

Cardiovascular Changes Related to Metabolic Syndrome: Evidence in Obese Zucker Rats

F1F0 ATP Synthase–Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline

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