P66shc and its role in ischemic cardiovascular diseases

Boengler, Kerstin; Bornbaum, Julia; Schlüter, Klaus‐Dieter; Schulz, Rainer

doi:10.1007/s00395-019-0738-x

Cited by 47 publications

(37 citation statements)

References 117 publications

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“…Intracellular ADP and oxygen gradients, as well as a local and region-specific increase in cellular Ca 2+ , may also contribute to the control of mitochondrial function, dynamics, and morphology, thus playing an important role in the formation of mitochondrial heterogeneity. Moreover, the specific role of the p66Shc protein in the cellular mechanisms leading to ROS increase, oxidative stress and activation of programmed cell death by apoptosis [103] during IR and other pathologies has been demonstrated [104,105,106]. The involvement of various protein kinase C (PKC) isoforms during redox stress (differing in their biochemical properties and sensitivities) produces a complex pattern of PKC signaling (Figure 3, [104]) potentially also contributing to mitochondrial heterogeneity.…”

Section: Mitochondrial Heterogeneity and Subpopulations: Possible mentioning

confidence: 99%

The Role of Mitochondria in the Mechanisms of Cardiac Ischemia-Reperfusion Injury

et al. 2019

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Mitochondria play a critical role in maintaining cellular function by ATP production. They are also a source of reactive oxygen species (ROS) and proapoptotic factors. The role of mitochondria has been established in many aspects of cell physiology/pathophysiology, including cell signaling. Mitochondria may deteriorate under various pathological conditions, including ischemia-reperfusion (IR) injury. Mitochondrial injury can be one of the main causes for cardiac and other tissue injuries by energy stress and overproduction of toxic reactive oxygen species, leading to oxidative stress, elevated calcium and apoptotic and necrotic cell death. However, the interplay among these processes in normal and pathological conditions is still poorly understood. Mitochondria play a critical role in cardiac IR injury, where they are directly involved in several pathophysiological mechanisms. We also discuss the role of mitochondria in the context of mitochondrial dynamics, specializations and heterogeneity. Also, we wanted to stress the existence of morphologically and functionally different mitochondrial subpopulations in the heart that may have different sensitivities to diseases and IR injury. Therefore, various cardioprotective interventions that modulate mitochondrial stability, dynamics and turnover, including various pharmacologic agents, specific mitochondrial antioxidants and uncouplers, and ischemic preconditioning can be considered as the main strategies to protect mitochondrial and cardiovascular function and thus enhance longevity.

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Section: Mitochondrial Heterogeneity and Subpopulations: Possible mentioning

confidence: 99%

The Role of Mitochondria in the Mechanisms of Cardiac Ischemia-Reperfusion Injury

et al. 2019

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“…Moreover, complex III of the mitochondrial respiratory chain generates ROS species through the ubiquinone-reactive sites, Q0 and Qi [51,52]. The redox activity of 66-kDa Src homology 2 domain-containing protein (p66Shc) within mitochondria has been shown to directly generate hydrogen peroxide through oxidation of cytochrome c without intermediate formation of superoxide anion [53,54]. The apoptosis-inducing factor (AIF) demonstrates NADH oxidase activity and generates superoxide and hydrogen peroxide [40,55].…”

Section: Oxidative Stressmentioning

confidence: 99%

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Toan

Zhou

2020

Aging

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Nutrient oversupply and mitochondrial dysfunction play central roles in nonalcoholic fatty liver disease (NAFLD). The mitochondria are the major sites of β-oxidation, a catabolic process by which fatty acids are broken down. The mitochondrial quality control (MQC) system includes mitochondrial fission, fusion, mitophagy and mitochondrial redox regulation, and is essential for the maintenance of the functionality and structural integrity of the mitochondria. Excessive and uncontrolled production of reactive oxygen species (ROS) in the mitochondria damages mitochondrial components, including membranes, proteins and mitochondrial DNA (mtDNA), and triggers the mitochondrial pathway of apoptosis. The functionality of some damaged mitochondria can be restored by fusion with normally functioning mitochondria, but when severely damaged, mitochondria are segregated from the remaining functional mitochondrial network through fission and are eventually degraded via mitochondrial autophagy, also called as mitophagy. In this review, we describe the functions and mechanisms of mitochondrial fission, fusion, oxidative stress and mitophagy in the development and progression of NAFLD.

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“… 2 The clinical importance of cardiomyocyte ischemia-reperfusion (I/R) injury has been widely acknowledged, because infarction size is a major determinant of patients’ long-term prognosis. 3 However, the I/R injury to coronary circulation and cardiac microvascular function still remain a major challenge in standard medical treatments of myocardial infarction, i.e., primary percutaneous coronary intervention or open heart surgery. 4 , 5 …”

Section: Introductionmentioning

confidence: 99%

SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury

Tan

Mui

Toan

et al. 2020

Molecular Therapy - Nucleic Acids

119

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Despite significant advances in the treatment of myocardial ischemia-reperfusion (I/R) injury, coronary circulation is a so far neglected target of cardioprotection. In this study, we investigated the molecular mechanisms underlying I/R injury to cardiac microcirculation. Using gene delivery, we analyzed microvascular protective effects of sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) on the reperfused heart and examined the role of SERCA in regulating mitochondrial quality control in cardiac microvascular endothelial cells (CMECs). Our data showed that SERCA overexpression attenuates lumen stenosis, inhibits microthrombus formation, reduces inflammation response, and improves endothelium-dependent vascular relaxation. In vitro experiments demonstrated that SERCA overexpression improves endothelial viability, barrier integrity, and cytoskeleton assembly in CMECs. Mitochondrial quality control, including mitochondrial fusion, mitophagy, bioenergetics, and biogenesis, were disrupted by I/R injury but were restored by SERCA overexpression. SERCA overexpression also restored mitochondrial quality control by inhibiting calcium overload, inactivating xanthine oxidase (XO), and reducing intracellular/mitochondrial reactive oxygen species (ROS). Administration of exogenous XO or a calcium channel agonist abolished the protective effects of SERCA overexpression on mitochondrial quality control and offset the beneficial effects of SERCA overexpression after cardiac microvascular I/R injury. These findings indicate that SERCA overexpression may be an effective approach to targeting cardiac microvascular I/R injury by regulating calcium/XO/ROS signaling and preserving mitochondrial quality control.

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P66shc and its role in ischemic cardiovascular diseases

Cited by 47 publications

References 117 publications

The Role of Mitochondria in the Mechanisms of Cardiac Ischemia-Reperfusion Injury

The Role of Mitochondria in the Mechanisms of Cardiac Ischemia-Reperfusion Injury

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

SERCA Overexpression Improves Mitochondrial Quality Control and Attenuates Cardiac Microvascular Ischemia-Reperfusion Injury

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