Distinct mPTP activation mechanisms in ischaemia–reperfusion: contributions of Ca2+, ROS, pH, and inorganic polyphosphate

Seidlmayer, Lea K.; Juettner, Vanessa V.; Kettlewell, Sarah; Pavlov, Evgeny; Blatter, Lothar A.; Dedkova, Elena N.

doi:10.1093/cvr/cvv097

Cited by 155 publications

(134 citation statements)

References 63 publications

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“…The lack of PTP re-opening as [Ca 2+ ] mito recovers might also be due to loss of mitochondrial Ca 2+ bound phosphate and polyphosphate, that may both promote PTP opening. 21, 35 Hence, tPTPs may also reset mitochondrial Ca 2+ buffering in a way that restores acute responsiveness of Ca-dependent dehydrogenase activation during cytosolic Ca 2+ changes, while limiting further PTP events.…”

Section: Discussionmentioning

confidence: 99%

Individual Cardiac Mitochondria Undergo Rare Transient Permeability Transition Pore Openings

Kwong

Molkentin

et al. 2016

Circulation Research

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Rationale Mitochondria produce ATP, especially critical for survival of highly aerobic cells such as cardiac myocytes. Conversely, opening of mitochondrial high-conductance and long-lasting permeability transition pores (mPTP) causes respiratory uncoupling, mitochondrial injury and cell death. However, low-conductance and transient mPTP openings (tPTP) might limit mitochondrial Ca2+ load and be cardioprotective, but direct evidence for tPTP in cells is limited. Objective To directly characterize tPTP occurrence during SR Ca2+ release in adult cardiac myocytes. Methods and Results Here, we measured tPTP directly as transient drops in mitochondrial [Ca2+] ([Ca2+]mito) and membrane potential (ΔΨm) in adult cardiac myocytes during cyclical sarcoplasmic reticulum Ca release, by simultaneous live imaging of 500-1,000 individual mitochondria. The frequency of tPTPs rose at higher [Ca2+]mito, [Ca2+]i, with 1 μM peroxide exposure and in myocyte from failing hearts. The tPTPs were suppressed by preventing mitochondrial Ca2+ influx, by mPTP inhibitor cyclosporine A, sanglifehrin and in cyclophilin D knockout mice. These tPTP events were 57 ± 5 s in duration, but were rare (occurring in <0.1% of myocyte mitochondria at any moment) such that the overall energetic cost to the cell is minimal. The tPTP pore size is much smaller than for permanent mPTP, as neither Rhod-2 nor calcien (600 Da) were lost. Thus, proteins and even molecules the size of NADH (663 Da) will be retained during these tPTP. Conclusions We conclude that tPTP openings (MitoWinks) may be molecularly related to pathological mPTP, but are likely to be normal physiological manifestation that benefits mitochondrial (and cell) survival by allowing individual mitochondria to reset themselves with little overall energetic cost.

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Section: Discussionmentioning

confidence: 99%

Individual Cardiac Mitochondria Undergo Rare Transient Permeability Transition Pore Openings

Kwong

Molkentin

et al. 2016

Circulation Research

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“…The cell dish was assembled with closed perfusion cell culture dish inserts (Warner Instrument) for solution changes during recording and then mounted onto the stage of a confocal microscopy (Nikon A1R). TMRM fluorescence (λ em 552 nm and λ ex 543 nm) was first recorded in oxygenated Tyrode buffer for 6 min as baseline and then simulated ischemia was initiated by exchanging normal Tyrode buffer with a simulated ischemia buffer containing (in mM) 20 2-deoxyglucose, 2 NaCN, 135 NaCl, 4 KCl, 1 MgCl 2 , 2 CaCl 2 , and 10 Hepes, pH 6.4 [38,40] through the inlet and outlet ports of the perfusion cell culture dish inserts. After 10 min incubation in simulated ischemia buffer, restoration of the control conditions was initiated by suffusing the cells with normal Tyrode buffer through the cell culture dish inserts over 8 min to wash out the simulated ischemia buffer.…”

Section: Methodsmentioning

confidence: 99%

Identity and function of a cardiac mitochondrial small conductance Ca 2+ -activated K + channel splice variant

Yang

Camara

Aldakkak

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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We provide evidence for location and function of a small conductance, Ca2+-activated K+ (SKCa) channel isoform 3 (SK3) in mitochondria (m) of guinea pig, rat and human ventricular myocytes. SKCa agonists protected isolated hearts and mitochondria against ischemia/reperfusion (IR) injury; SKCa antagonists worsened IR injury. Intravenous infusion of a SKCa channel agonist/antagonist, respectively, in intact rats was effective in reducing/enhancing regional infarct size induced by coronary artery occlusion. Localization of SK3 in mitochondria was evidenced by Western blot of inner mitochondrial membrane, immunocytochemical staining of cardiomyocytes, and immunogold labeling of isolated mitochondria. We identified a SK3 splice variant in guinea pig (SK3.1, aka SK3a) and human ventricular cells (SK3.2) by amplifying mRNA, and show mitochondrial expression in mouse atrial tumor cells (HL-1) by transfection with full length and truncated SK3.1 protein. We found that the Nterminus is not required for mitochondrial trafficking but the C-terminus beyond the Ca2+ calmodulin binding domain is required for Ca2+ sensing to induce mK+ influx and/or promote mitochondrial localization. In isolated guinea pig mitochondria and in SK3 overexpressed HL-1 cells, mK+ influx was driven by adding CaCl2. Moreover, there was a greater fall in membrane potential (ΔΨm), and enhanced cell death with simulated cell injury after silencing SK3.1 with siRNA. Although SKCa channel opening protects the heart and mitochondria against IR injury, the mechanism for favorable bioenergetics effects resulting from SKCa channel opening remains unclear. SKCa channels could play an essential role in restraining cardiac mitochondria from inducing oxidative stress-induced injury resulting from mCa2+ overload.

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“…After the biochemical changes that occur during ischemia (increase in ROS, Ca 2ϩ , and P i levels and decrease in ATP content and membrane potential), the mPTP was primed but remained closed because of the low intracellular pH. More recently, Seidlmayer et al (168) demonstrated that cardiac ischemia is associated with transient mPTP opening to protect cells from Ca 2ϩ accumulation and ROS production (Fig. 3).…”

Section: Chronology Of Events At the Level Of Skeletal Muscle Fiber Cmentioning

confidence: 96%

“…In parallel, ischemia participates in production of ROS, mainly O 2 ·Ϫ and H 2 O 2 (5,159,168). Few studies have examined the effects of ischemia alone in skeletal muscle by measuring either ROS production directly or oxidative stress products.…”

Section: Chronology Of Events At the Level Of Skeletal Muscle Fiber Cmentioning

confidence: 99%

“…Lactate, H ϩ , and precursors of adenine nucleotide metabolism are also washed out (66,133,135). Extra-and intracellular pH are rapidly restored via activation of several exchangers at the beginning of reperfusion (37,118), inducing lethal cell injury through mPTP opening (168). Indeed, this rapid regularization of acidosis plays an essential role in reperfusion injury.…”

Section: ϩmentioning

confidence: 99%

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Chronology of mitochondrial and cellular events during skeletal muscle ischemia-reperfusion

Paradis

Charles

Meyer

et al. 2016

American Journal of Physiology-Cell Physiology

127

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Peripheral artery disease (PAD) is a common circulatory disorder of the lower limb arteries that reduces functional capacity and quality of life of patients. Despite relatively effective available treatments, PAD is a serious public health issue associated with significant morbidity and mortality. Ischemia-reperfusion (I/R) cycles during PAD are responsible for insufficient oxygen supply, mitochondriopathy, free radical production, and inflammation and lead to events that contribute to myocyte death and remote organ failure. However, the chronology of mitochondrial and cellular events during the ischemic period and at the moment of reperfusion in skeletal muscle fibers has been poorly reviewed. Thus, after a review of the basal myocyte state and normal mitochondrial biology, we discuss the physiopathology of ischemia and reperfusion at the mitochondrial and cellular levels. First we describe the chronology of the deleterious biochemical and mitochondrial mechanisms activated by I/R. Then we discuss skeletal muscle I/R injury in the muscle environment, mitochondrial dynamics, and inflammation. A better understanding of the chronology of the events underlying I/R will allow us to identify key factors in the development of this pathology and point to suitable new therapies. Emerging data on mitochondrial dynamics should help identify new molecular and therapeutic targets and develop protective strategies against PAD.peripheral artery disease; ischemia-reperfusion; skeletal muscle; mitochondria; oxidative stress PERIPHERAL ARTERY DISEASE (PAD) refers to a common circulatory disorder of the lower limb caused by chronic narrowing of the arteries (e.g., stenosis and occlusion) or atherosclerosis. PAD represents a broad spectrum of disease severity, ranging from asymptomatic disease to frequent pain when walking (i.e., intermittent claudication or limping) or critical limb ischemia associated with decubitus pain and/or ulcers (114,126).PAD is known to be associated with reduced functional capacity and quality of life. It is a major cause of limb amputation, as well as an increased risk factor for myocardial infarction, stroke, and death. The incidence of PAD varies with age, from 3-10% in young people to 15-20% in people Ͼ70 yr of age, and is asymptomatic in 40% of the cases (1), with greater prevalence among men. The major PAD risk factors, including smoking, diabetes mellitus, dyslipidemia, hypertension, and obesity, are the same as those for cardiovascular and cerebrovascular diseases (35).Three main complementary treatment options improve the functional status and other clinical outcomes in PAD patients (54). 1) Optimization of medical therapy (i.e., pharmacotherapy) reduces the risk of cardiac ischemia, increases the distance a patient can walk, and improves the functional capacity of patients. 2) When possible, exercise training, a noninvasive and nonpharmacological therapy, improves walking ability and has protective effects in patients with PAD characterized by intermittent claudication and infrainguinal lesions...

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Distinct mPTP activation mechanisms in ischaemia–reperfusion: contributions of Ca2+, ROS, pH, and inorganic polyphosphate

Abstract: Transient Ca(2+)/polyP-mediated mPTP opening during ischaemia may serve to protect cells against cytosolic Ca(2+) overload, whereas ROS/pH-mediated sustained mPTP opening on reperfusion induces cell death.

Cited by 155 publications

References 63 publications

Individual Cardiac Mitochondria Undergo Rare Transient Permeability Transition Pore Openings

Individual Cardiac Mitochondria Undergo Rare Transient Permeability Transition Pore Openings

Identity and function of a cardiac mitochondrial small conductance Ca 2+ -activated K + channel splice variant

Chronology of mitochondrial and cellular events during skeletal muscle ischemia-reperfusion

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