assessment-open-probability-mitochondrial-permeability-transition

Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess

The mitochondrial permeability transition pore (mPTP) is a voltage-gated, nonselective, inner mitochondrial membrane (IMM) mega-channel important in ...

Columbia University Medical Center

Commonly used anesthetics have been shown to disrupt neurodevelopment in preclinical models. It has been proposed that such anesthesia-induced neurotoxicity is mediated by apoptotic neurodegeneration in the immature brain. Low dose carbon monoxide (CO) exerts cytoprotective properties and we have previously demonstrated that CO inhibits isoflurane-induced apoptosis in the developing murine brain. Here we utilized anti-apoptotic concentrations of CO to delineate the role of apoptotic neurodegeneration in anesthesia-induced neurotoxicity by assessing the effect of CO on isoflurane-induced defects in neurodevelopment.

Carbon monoxide incompletely prevents isoflurane-induced defects in murine neurodevelopment.

The data presented here detail the changes in size, cellular content, and neuronal density of the developing brain over time with respect to sex in C57Bl/6 mice following neonatal exposure to isoflurane, carbon monoxide, or their combination. Specifically, brain weight- and brain volume-to-body weight ratios are presented, representative immunoblots of whole brain cell-specific protein content are depicted, and quantification of the number of neurons in the primary somatosensory cortex and CA3 region of the hippocampus are shown. Three discrete postnatal time points are represented: P7 (prior to exposure), P14 (one-week post exposure), and P42-56 (5-7 weeks post exposure). Major findings from the data presented here are reported in the manuscript "Carbon Monoxide Incompletely Prevents Isoflurane-induced Defects in Murine Neurodevelopment" (Wang et al., in press) [1].

Data on the effect of sex on the size, cellular content, and neuronal density of the developing brain in mice exposed to isoflurane and carbon monoxide.

Fragile X syndrome (FXS) is the leading known inherited intellectual disability and the most common genetic cause of autism. The full mutation results in transcriptional silencing of the Fmr1 gene and loss of fragile X mental retardation protein (FMRP) expression. Defects in neuroenergetic capacity are known to cause a variety of neurodevelopmental disorders. Thus, we explored the integrity of forebrain mitochondria in Fmr1 knockout mice during the peak of synaptogenesis. We found inefficient thermogenic respiration due to futile proton leak in Fmr1 KO mitochondria caused by coenzyme Q (CoQ) deficiency and an open cyclosporine-sensitive channel. Repletion of mitochondrial CoQ within the Fmr1 KO forebrain closed the channel, blocked the pathological proton leak, restored rates of protein synthesis during synaptogenesis, and normalized the key phenotypic features later in life. The findings demonstrate that FMRP deficiency results in inefficient oxidative phosphorylation during the neurodevelopment and suggest that dysfunctional mitochondria may contribute to the FXS phenotype.

Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome.

Mitochondrial permeability transition pore (mPTP) closure triggers cardiomyocyte differentiation during development while pathological opening causes cell death during myocardial ischemia-reperfusion and heart failure. Ubiquinone modulates the mPTP; however, little is known about its mechanistic role in health and disease. We previously found excessive proton leak in newborn Fmr1 KO mouse forebrain caused by ubiquinone deficiency and increased open mPTP probability. Because of the physiological differences between the heart and brain during maturation, we hypothesized that developing Fmr1 KO cardiomyocyte mitochondria would demonstrate dissimilar features.

The newborn Fmr1 knockout mouse: a novel model of excess ubiquinone and closed mitochondrial permeability transition pore in the developing heart.

Insights image for "The newborn Fmr1 knockout mouse: a novel model of excess ubiquinone and closed mitochondrial permeability transition pore in the developing heart".

Anesthetics such as isoflurane are known to cause apoptosis in the developing mammalian brain. However, isoflurane may have protective effects on the heart via relieving ischemia and downregulating genes related to apoptosis. Ischemic preconditioning, e.g. through the use of low levels of carbon monoxide (CO), has promise in preventing ischemia-reperfusion injury and cell death. However, it is still unclear how it either triggers the stress response in neonatal hearts. For this reason, thirty-three microRNAs (miRNAs) known to be differentially expressed following anesthesia and/or ischemic or hypoxic heart damage were investigated in the hearts from neonatal mice exposed to isoflurane or low level of CO, using an air-exposed control group. Only miR-93-5p increased with isoflurane exposure, which may be associated with the suppression of cell death, autophagy, and inflammation. By contrast, twelve miRNAs were differentially expressed in the heart following CO treatment. Many miRNAs previously shown to be responsible for suppressing cell death, autophagy, and myocardial hypertrophy were upregulated (e.g., 125b-3p, 19-3p, and 21a-5p). Finally, some miRNAs (miR-103-3p, miR-1a-3p, miR-199a-1-5p) which have been implicated in regulating energy balance and cardiac contraction were also differentially expressed. Overall, this study demonstrated that CO-mediated miRNA regulation may promote ischemic preconditioning and cardioprotection based on the putative protective roles of the differentially expressed miRNAs explored herein and the consistency of these results with those that have shown positive effects of CO on heart viability following anesthesia and ischemia-reperfusion stress.

Isoflurane and low-level carbon monoxide exposures increase expression of pro-survival miRNA in neonatal mouse heart.

Propofol infusion syndrome (PRIS) is a potentially lethal consequence of long-term propofol administration. Children are vulnerable and cardiac involvement is often prominent and associated with mortality. We aimed to determine the mechanism of propofol toxicity in newborn mice, hypothesizing that propofol would induce discrete defects within immature cardiac mitochondria.

Aili Wang

Department of Anesthesiology

Columbia University Medical Center

Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess