Mitochondria as a Target for Neurotoxins and Neuroprotective Agents (original) (raw)
Related papers
Amyloid β-peptide promotes permeability transition pore in brain mitochondria
Bioscience Reports, 2001
In this work the effect of the neurotoxic amino acid sequence, Aβ 25-35 , on brain mitochondrial permeability transition pore (PTP) was studied. For the purpose, the mitochondrial transmembrane potential (∆Ψm), mitochondrial respiration and the calcium fluxes were examined. It was observed that Aβ 25-35 , in the presence of Ca 2+ , decreased the ∆Ψm, the capacity of brain mitochondria to accumulate calcium and led to a complete uncoupling of the respiration. However, the reverse sequence of the peptide Aβ 25-35 (Aβ 35-25) did not promote the PTP. The alterations promoted by Aβ 35-25 and͞or Ca 2+ could be reversed when Ca 2+ was removed by EGTA or when ADP plus oligomycin were present. The pretreatment with CsA or ADP plus oligomycin prevented the ∆Ψm drop and preserved the capacity of mitochondria to accumulate Ca 2+. These results suggest that Aβ 25-35 can promote the PTP induced by Ca 2+ .
Pharmacological inhibition of mitochondrial membrane permeabilization for neuroprotection
Experimental Neurology, 2009
Recent data have provided important clues about the molecular mechanisms underlying certain neurodegenerative diseases. Most cell death in vertebrates proceeds via the mitochondrial pathway of apoptosis. Mitochondria contain proapoptotic factors such as cytochrome c and AIF in their intermembrane space. Furthermore, mitochondrial membrane permeabilization (MMP) is a critical event during apoptosis, representing the "point of no return" of the lethal process. Modern medicine is developing an increasing number of drugs for neurodegenerative disease, but no neuroprotective treatment has yet been established. While current treatments temporarily alleviate symptoms, they do not halt disease progression. This paper briefly reviews the pharmacological inhibition of mitochondrial membrane permeabilization for neuroprotection.
Neurodegener Dis, 2011
roid derivative shown to protect neuronal cells against A  1-42 -induced neurotoxicity. Further experiments revealed that the mitotoxic effect of A  1-42 is specific to its primary amino acid sequence and suggested that it may be also related to its tertiary structure. Importantly, the mitotoxic effect of A  1-42 was not restricted to brain cells, indicating that it is not cell-or tissue-specific. Conclusion: Taken together, these results suggest that extracellular A  1-42 targets neuronal mitochondria to exert its toxic effects.
Neurodegenerative Diseases, 2011
roid derivative shown to protect neuronal cells against A  1-42 -induced neurotoxicity. Further experiments revealed that the mitotoxic effect of A  1-42 is specific to its primary amino acid sequence and suggested that it may be also related to its tertiary structure. Importantly, the mitotoxic effect of A  1-42 was not restricted to brain cells, indicating that it is not cell-or tissue-specific. Conclusion: Taken together, these results suggest that extracellular A  1-42 targets neuronal mitochondria to exert its toxic effects.
Mitochondrial membrane permeabilisation by amyloid aggregates and protection by polyphenols
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013
Alzheimer's disease and Parkinson's disease are neurodegenerative disorders characterised by the misfolding of proteins into soluble prefibrillar aggregates. These aggregate complexes disrupt mitochondrial function, initiating a pathophysiological cascade leading to synaptic and neuronal degeneration. In order to explore the interaction of amyloid aggregates with mitochondrial membranes, we made use of two in vitro model systems, namely: (i) lipid vesicles with defined membrane compositions that mimic those of mitochondrial membranes, and (ii) respiring mitochondria isolated from neuronal SH-SY5Y cells. External application of soluble prefibrillar forms, but not monomers, of amyloid-beta (Aβ 42 peptide), wild-type α-synuclein (α-syn), mutant α-syn (A30P and A53T) and tau-441 proteins induced a robust permeabilisation of mitochondrial-like vesicles, and triggered cytochrome c release (CCR) from isolated mitochondrial organelles. Importantly, the effect on mitochondria was shown to be dependent upon cardiolipin, an anionic phospholipid unique to mitochondria and a well-known key player in mitochondrial apoptosis. Pharmacological modulators of mitochondrial ion channels failed to inhibit CCR. Thus, we propose a generic mechanism of thrilling mitochondria in which soluble amyloid aggregates have the intrinsic capacity to permeabilise mitochondrial membranes, without the need of any other protein. Finally, six small-molecule compounds and black tea extract were tested for their ability to inhibit permeation of mitochondrial membranes by Aβ 42 , α-syn and tau aggregate complexes. We found that black tea extract and rosmarinic acid were the most potent mito-protectants, and may thus represent important drug leads to alleviate mitochondrial dysfunction in neurodegenerative diseases.
Mitochondrial dysfunction: different routes to Alzheimer's disease therapy
Oxidative medicine and cellular longevity, 2014
Mitochondria are dynamic ATP-generating organelle which contribute to many cellular functions including bioenergetics processes, intracellular calcium regulation, alteration of reduction-oxidation potential of cells, free radical scavenging, and activation of caspase mediated cell death. Mitochondrial functions can be negatively affected by amyloid β peptide (Aβ), an important component in Alzheimer's disease (AD) pathogenesis, and Aβ can interact with mitochondria and cause mitochondrial dysfunction. One of the most accepted hypotheses for AD onset implicates that mitochondrial dysfunction and oxidative stress are one of the primary events in the insurgence of the pathology. Here, we examine structural and functional mitochondrial changes in presence of Aβ. In particular we review data concerning Aβ import into mitochondrion and its involvement in mitochondrial oxidative stress, bioenergetics, biogenesis, trafficking, mitochondrial permeability transition pore (mPTP) formation,...
Mitochondria and Alzheimer's Disease Editorial Volume 1 Issue 5 -2014
2018
On the basis of the substantial role that mitochondrial pathology and mitochondrial genetic defects seems to play in the pathogenetic cascade of AD new strategies inducing protection to mitochondria by inhibition of mitochondrial β-oxidation, inhibition of ERK-DLP1 signaling and mitochondrial division [93], regulating calcium trafficking in the endoplasmic reticulum or via mitochondria and controlling mitochondrial calcium uptake by the administration of efficient antioxidant factors and natural antioxidants or using nanotechnology and supporting the neuroplasticity may be introduced in the treatment of early cases of Alzheimer’s disease.
Mitochondrial toxins and neurodegenerative diseases
Frontiers in Bioscience, 2007
2. Mitochondrial toxin involved in neurodegeneration 3. Toxin that produced a neurodegeneration like that found in parkinson's disease 3.1. 1. Methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) 3.2. Tetrahydroisoquinoline derivatives as possible endogenous neurotoxins 3.2.1. 1. Methyl-1,2,3,4-tetrahydroisoquinoline as neuroprotector of dopaminergic systems 3.3. Rotenone 3.3.1. In vivo rotenone models of Parkinson's disease 3.3.2. Rotenone and oxidative stress 3.3.3. Rotenone and the proteasome. 3.3.4. Rotenone and apoptosis 3.3.5. Rotenone and the dopaminergic system 3.4. Other inhibitors of Complex I 4. Toxins that produced a neurodegeneration like that found in Huntington disease: Inhibitor of succinate dehydrogenase 4.1. Pathways of cells death induced by 3-NPA.
The mitochondrial permeability transition in neurologic disease
Neurochemistry International, 2007
Mitochondria, being the principal source of cellular energy, are vital for cell life. Yet, ironically, they are also major mediators of cell death, either by necrosis or apoptosis. One means by which these adverse effects occur is through the mitochondrial permeability transition (mPT) whereby the inner mitochondrial membrane suddenly becomes excessively permeable to ions and other solutes, resulting in a collapse of the inner membrane potential, ultimately leading to energy failure and cell necrosis. The mPT may also bring about the release of various factors known to cause apoptotic cell death. The principal factors leading to the mPT are elevated levels of intracellular Ca 2+ and oxidative stress. Characteristically, the mPT is inhibited by cyclosporin A. This article will briefly discuss the concept of the mPT, its molecular composition, its inducers and regulators, agents that influence its activity and describe the consequences of its induction. Lastly, we will review its potential contribution to acute neurological disorders, including ischemia, trauma, and toxic-metabolic conditions, as well as its role in chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Published by Elsevier Ltd.
Mitochondria: a therapeutic target in neurodegeneration
Biochimica et biophysica acta, 2010
Mitochondrial dysfunction has long been associated with neurodegenerative disease. Therefore, mitochondrial protective agents represent a unique direction for the development of drug candidates that can modify the pathogenesis of neurodegeneration. This review discusses evidence showing that mitochondrial dysfunction has a central role in the pathogenesis of Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis. We also debate the potential therapeutic efficacy of metabolic antioxidants, mitochondria-directed antioxidants and Szeto–Schiller (SS) peptides. Since these compounds preferentially target mitochondria, a major source of oxidative damage, they are promising therapeutic candidates for neurodegenerative diseases. Furthermore, we will briefly discuss the novel action of the antihistamine drug Dimebon on mitochondria.