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PubMed2002

Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs?

Alzheimer disease (AD) is defined pathologically and diagnostically defined by amyloid-beta senile plaques and neurofibrillary tangles (NFT) composed of tau. From the time of their original description nearly a century ago, a major focus has been to understand the role that these lesions play in the pathogenesis of the disease. The majority favors the notion that these lesions cause the disease and therefore attempts at therapeutic intervention are focused on preventing lesions formation. However, this rationale may be misguided since new evidence from our laboratories and others suggest that the lesions not only occur as a by-product of the fundamental disease process but also that they may be protective.

Aging↗
PubMed1999

Protective effect of P. fraternus against ethanol-induced mitochondrial dysfunction.

Chronic ethanol consumption (10 g per kg body weight) significantly decreased the rate of respiration, P/O ratio, and respiratory control ratio (RCR). The activities of NADH dehydrogenase and cytochrome oxidase were significantly decreased in submitochondrial particles by ethanol administration compared to control. No significant difference was observed in membrane potential of submitochondrial particles. Cytochrome b, c and aa3 content of mitochondria were significantly decreased by ethanol feeding. Ethanol-induced inhibition on rate of respiration, P/O ratio, and RCR was relieved to a great extent by the administration of the aqueous extract of Phyllanthus fraternus (100 mg dry powder of the plant per kg body weight) along with ethanol. The decrease in the content of cytochromes due to ethanol administration was revived partially by aqueous extract of P. fraternus.

Animals↗
PubMed2002

Heart and breast muscle mitochondrial dysfunction in pulmonary hypertension syndrome in broilers (Gallus domesticus).

This study was conducted to determine function and defects in electron transport in muscle mitochondria of meat chickens (broilers) with pulmonary hypertension syndrome (PHS). The respiratory control ratio (RCR, indicative of respiratory chain coupling) was higher in the control than in PHS breast and heart muscle mitochondria, but there were no differences in the ADP/O (an index of oxidative phosphorylation). Sequential additions of ADP improved the RCR in the control breast muscle mitochondria and the ADP/O in PHS breast and heart muscle mitochondria. Basal hydrogen peroxide production, (an indicator of electron leak), was higher in PHS breast and heart muscle mitochondria than in controls and differences in electron leak in PHS mitochondria were magnified by inhibiting electron transport at Complex I and III (cyt b(562)). Complex I activity was lower in PHS heart mitochondria but there was no difference in Complex II activity. Thus, compared to controls, PHS mitochondria exhibited site-specific defects in electron transport within Complex I and III that could contribute to lower respiratory chain coupling. Additionally, it appears that healthy broilers may exhibit higher basal levels of electron leak compared to other avian species. Together, these findings provide insight into inefficient cellular use of oxygen that may contribute to the development of PHS in broilers.

Animals↗
PubMed2001

N-Acetylaspartate reduction as a measure of injury severity and mitochondrial dysfunction following diffuse traumatic brain injury.

N-Acetylaspartate (NAA) is considered a neuron-specific metabolite and its reduction a marker of neuronal loss. The objective of this study was to evaluate the time course of NAA changes in varying grades of traumatic brain injury (TBI), in concert with the disturbance of energy metabolites (ATP). Since NAA is synthesized by the mitochondria, it was hypothesized that changes in NAA would follow ATP. The impact acceleration model was used to produce three grades of TBI. Sprague-Dawley rats were divided into the following four groups: sham control (n = 12); moderate TBI (n = 36); severe TBI (n = 36); and severe TBI coupled with hypoxia-hypotension (n = 16). Animals were sacrificed at different time points ranging from 1 min to 120 h postinjury, and the brain was processed for high-performance liquid chromatography (HPLC) analysis of NAA and ATP. After moderate TBI, NAA reduced gradually by 35% at 6 h and 46% at 15 h, accompanied by a 57% and 45% reduction in ATP. A spontaneous recovery of NAA to 86% of baseline at 120 h was paralleled by a restoration in ATP. In severe TBI, NAA fell suddenly and did not recover, showing critical reduction (60%) at 48 h. ATP was reduced by 70% and also did not recover. Maximum NAA and ATP decrease occurred with secondary insult (80% and 90%, respectively, at 48 h). These data show that, at 48 h post diffuse TBI, reduction of NAA is graded according to the severity of insult. NAA recovers if the degree of injury is moderate and not accompanied by secondary insult. The highly similar time course and correlation between NAA and ATP supports the notion that NAA reduction is related to energetic impairment.

Adenosine Triphosphate↗
PubMed2003

All-trans retinoic acid (atRA) differentially induces apoptosis in matched primary and metastatic melanoma cells -- a speculation on damage effect of atRA via mitochondrial dysfunction and cell cycle redistribution.

All-trans retinoic acid (atRA) has been suggested to exert its cytotoxicity via apoptosis but the mechanisms behind the damage effects have not been fully understood. In this study, we investigated the cytotoxic effects of atRA in eleven primary and matched metastatic cutaneous melanoma cell lines. All the primary and metastatic melanoma cell lines examined expressed the retinoic acid receptors. The cultured melanoma cells treated with atRA showed dysfunction of mitochondria and altered cell cycle distribution, inhibited cell proliferation and apoptosis. The cytotoxic effects of atRA were dose- and time-dependent. The dysfunction of mitochondria and induction of apoptosis were more pronounced in the primary tumor cells than in the metastatic cell lines from the same patients. The data indicate that the cytotoxic effect of atRA was mediated through dysfunction of mitochondria, alterations in cell cycle and induction of apoptosis. Melanoma in early stage may have better response to atRA adjuvant therapy than the melanoma in late stage, suggesting the early utility of atRA in melanoma chemotherapy.

Apoptosis↗
PubMed1988

Kinetic evidence for a heart mitochondrial pore activated by Ca2+, inorganic phosphate and oxidative stress. A potential mechanism for mitochondrial dysfunction during cellular Ca2+ overload.

Evidence that the Ca2+-induced permeabilization of mitochondria is attributable to a reversible Ca2+-activated pore [Al Nasser & Crompton (1986) Biochem. J. 239, 19-29] has been further investigated. Permeabilization is induced in a wholly synergistic manner by either Ca2+ plus phosphate or Ca2+ plus tert-butyl hydroperoxide. When permeabilization is complete, extramitochondrial [14C]sucrose equilibrates with the matrix space with a half-time of about 800 ms; [14C]mannitol equilibrates at least threefold faster. Permeabilization is essentially fully reversed on Ca2+ chelation with EGTA, when the half time for [14C]sucrose equilibration is increased 600-1400-fold (to 550-1150 s). A pulsed-flow [14C]solute-entrapment technique has been developed to measure the kinetics of EGTA-induced resealing. The technique incorporates a suitable choice of [14C]solute and an appropriate model for data analysis, and is competent to measure permeation state changes occurring in 100 ms. The data obtained are consistent with exponential resealing of mitochondria in which pores of any single mitochondria close with a high degree of synchrony. The rate of resealing is increased about eight-fold by ADP (half-time approximately 1 s; Km approximately 30 microM). CoA, Mg2+, AMP and also ATP, when account is taken of ADP arising by hydrolysis, are essentially ineffective. It is concluded that heart mitochondria do contain a pore whose permeation state is controlled over an approximate 1000-fold range by Ca2+ and other factors including phosphate, oxidative stress and ADP. The possible involvement of the pore in reoxygenation-induced injury in heart is discussed.

Adenosine Diphosphate↗
PubMed2000

Retardation of cation channel deactivation by mitochondrial dysfunction in adrenal medullary cells.

The mechanism for cyanide (CN) activation of a nonselective cation (NS) channel coupled with a muscarinic receptor in a guinea pig chromaffin cell was studied with the perforated-patch method. Bath application of a protein kinase inhibitor resulted in a dose-dependent inhibition of muscarine-induced current (I(M)) but had no apparent effect on the CN-induced current (I(CN)). On the other hand, production of I(CN) occluded muscarine activation of NS channels in an amplitude-dependent manner. Deactivation of I(M) after washout was retarded while I(CN) was also active, and the extent of the retardation increased with an increase in the relative production of I(CN) on muscarinic stimulation. Restoration of Na(+) pump activity from CN suppression was conspicuously retarded below 19-20 degrees C, and the apparent diminution of I(M) and I(CN) after washout was retarded in parallel with a decrease in temperature. The results suggest that CN activation of NS channels is due to suppression of deactivation of the channel.

Adrenal Medulla↗