Mitochondria from a mouse model of the human infantile neuroaxonal dystrophy (INAD) with genetic defects in VIA iPLA 2 have disturbed Ca 2+ regulation with reduction in Ca 2+ capacity

Strokin, Mikhail; Reiser, Georg

doi:10.1016/j.neuint.2016.07.002

Cited by 10 publications

(4 citation statements)

References 30 publications

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“…In the past decade plenty of evidence was obtained, which confirmed earlier knowledge that the impairments of mitochondrial Ca 2+ handling, both uptake and efflux, constitute molecular basis of several cardiovascular, neurodegenerative diseases, and other pathophysiological conditions [6][7][8].…”

supporting

confidence: 54%

Functional activity of permeability transition pore in energized and deenergized rat liver mitochondria

Акопова¹,

Kolchinskaya²,

Kolchinskaya³

2020

Ukr.Biochem.J

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permeability transition pore (mpTp) opening was studied under energized and deenergized conditions in rat liver mitochondria, and the effect of membrane depolarization on mPTP activity was evaluated. To assess mpTp activity, cyclosporine-sensitive swelling and cyclosporine sensitive ca 2+ efflux from mitochondria was studied using light absorbance techniques. In energized mitochondria, mpTp opening in subconductance states, at [ca 2+ ] ≤ K a , contributed positively to the rate of respiration, without affecting ΔΨ m . Threshold ca 2+ concentrations were found, which excess resulted in fast mitochondrial depolarization upon mpTp opening. An estimate of mpTp activity by cyclosporine-sensitive ca 2+ transport under energized and deenergized conditions showed that membrane depolarization by protonophore cccp essentially increased initial rate (V 0 ), at simultaneous decrease of the half-time (t 1/2 ) of ca 2+ efflux, which indicated mPTP activation, as compared to energized mitochondria. however, only partial release of ca 2+ via mpTp upon membrane depolarization was observed. With the use of selective blockers of ca 2+ uniporter and mpTp, ruthenium red (rr) and cyclosporine A (csA), partial contribution of ca 2+ uniporter and mpTp in ca 2+ transport was found. "Titration" of ca 2+ transport by adding RR at different times from the onset of depolarization showed that depolarization dramatically reduced "life span" of mpTp as compared to energized mitochondria, which agreed with the kinetic characteristics of csA-sensitive ca 2+ transport after the abolition of ΔΨ m . ca 2+ added from the outer side of mitochondrial membrane produced dual effect on mPTP activity: activation at the onset of depolarization, but consequent promotion of mPTP closure. Based on the experiments, it was concluded that mitochondrial energization was required for prolonged mpTp functioning in sub-conductance states, whereas membrane depolarization promoted the transition of mpTp to inactive state during calcium release from mitochondria. k e y w o r ds: rat liver mitochondria, calcium, permeability transition pore, ca 2+ transport, membrane potential.

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supporting

confidence: 54%

Functional activity of permeability transition pore in energized and deenergized rat liver mitochondria

Акопова¹,

Kolchinskaya²,

Kolchinskaya³

2020

Ukr.Biochem.J

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“…Several iPLA2β KO mice models showed disturbances in brain phospholipid metabolism and in Ca 2+ signaling in astrocytes associated with mitochondrial impairment [ 112 , 113 ]. The addition of disturbance phospholipids ameliorated the disturbances and partially restored the mitochondrial function [ 114 , 115 , 116 ].…”

Section: Nbia Types Related To Lipid Metabolism and Membrane Remodmentioning

confidence: 99%

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

et al. 2020

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The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes PANK2, PLA2G6, WDR45, C19ORF12, FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17. Nonetheless, many patients remain without a conclusive genetic diagnosis, which shows that there must be additional as yet undiscovered NBIA genes. In line with this, isolated cases of known monogenic disorders, and also, new genetic diseases, which present with abnormal brain iron phenotypes compatible with NBIA, have been described. Several pathways are involved in NBIA syndromes: iron and lipid metabolism, mitochondrial dynamics, and autophagy. However, many neurodegenerative conditions share features such as mitochondrial dysfunction and oxidative stress, given the bioenergetics requirements of neurons. This review aims to describe the existing link between the classical ten NBIA forms by examining their connection with mitochondrial impairment as well as oxidative stress and neuroinflammation.

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“…In recent years, deficiency in iPLA2β has been reported to elevate mitochondrial lipid peroxidation, resulting in mitochondrial dysfunction [ 60 ]. Mutation of this PLA2 also results in reduction of mitochondrial potential, leading to attenuation of calcium uptake and calcium retention capacity in mitochondria [ 61 ]. Studies on iPLA2 have been aided by the specific inhibitor, bromoenol lactone (BEL).…”

Section: Structure and Function Of Ipla2mentioning

confidence: 99%

Dynamic Role of Phospholipases A2 in Health and Diseases in the Central Nervous System

Sun

Geng

Teng

et al. 2021

Cells

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Phospholipids are major components in the lipid bilayer of cell membranes. These molecules are comprised of two acyl or alkyl groups and different phospho-base groups linked to the glycerol backbone. Over the years, substantial interest has focused on metabolism of phospholipids by phospholipases and the role of their metabolic products in mediating cell functions. The high levels of polyunsaturated fatty acids (PUFA) in the central nervous system (CNS) have led to studies centered on phospholipases A2 (PLA2s), enzymes responsible for cleaving the acyl groups at the sn-2 position of the phospholipids and resulting in production of PUFA and lysophospholipids. Among the many subtypes of PLA2s, studies have centered on three major types of PLA2s, namely, the calcium-dependent cytosolic cPLA2, the calcium-independent iPLA2 and the secretory sPLA2. These PLA2s are different in their molecular structures, cellular localization and, thus, production of lipid mediators with diverse functions. In the past, studies on specific role of PLA2 on cells in the CNS are limited, partly because of the complex cellular make-up of the nervous tissue. However, understanding of the molecular actions of these PLA2s have improved with recent advances in techniques for separation and isolation of specific cell types in the brain tissue as well as development of sensitive molecular tools for analyses of proteins and lipids. A major goal here is to summarize recent studies on the characteristics and dynamic roles of the three major types of PLA2s and their oxidative products towards brain health and neurological disorders.

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Mitochondria from a mouse model of the human infantile neuroaxonal dystrophy (INAD) with genetic defects in VIA iPLA 2 have disturbed Ca 2+ regulation with reduction in Ca 2+ capacity

Cited by 10 publications

References 30 publications

Functional activity of permeability transition pore in energized and deenergized rat liver mitochondria

Functional activity of permeability transition pore in energized and deenergized rat liver mitochondria

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

Dynamic Role of Phospholipases A2 in Health and Diseases in the Central Nervous System

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