MitoNews, Volume 8, Issue 10

Abcam: discover more

Hormonal regulation of mitochondria, October 2012

Edited by James Murray, PhD.

Thousands of researchers around the world are studying the connections between mitochondria, metabolism and disease. MitoNews summarizes a selection of the latest published findings and highlights how Abcam's MitoSciences range of research tools has contributed to this effort. The full list of 61 original research papers published this month using the MitoSciences range of products can be found here.


Past issues are available for review in the archives.


    Table of Contents

    I. Hormonal regulation of mitochondria

    II. Interaction of beta-amyloid (Abeta) and mitochondria

I. Hormonal regulation of mitochondria


Estradiol (E2 or 17β-estradiol) is a steroid hormone derived from cholesterol. It is the major estrogen, a potent sex hormone and produced by the adrenal cortex, ovaries and testes. Estrogens affect a number of different cell types and tissues including the reproductive, cardiovascular, nervous, immune, bone, gut and respiratory systems.


There are two estrogen receptors, ERα and ERβ which reside in both the cytoplasm and nucleus. However it has been proposed that an estradiol receptor exists, or perhaps simply ERβ, that is associated with mitochondria. Two papers this month use MitoSciences antibodies to show the effects of estradiol on mitochondrial function and biogenesis.


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition that may be caused by oxidative stress, mitochondrial dysfunction and apoptosis. In females higher levels of estradiol may be a protective factor in the development of this disease. For example, ALS is more common in age matched men than women. Also in the ALS animal model, SOD1 G93A, females have a slower disease progression than males or ovarectomized females. An understanding of the mechanism of estradiol protection, and how this relates to mitochondrial function is unclear.


This month Kim et al. showed that a cross of G93A-SOD1 mice with a mitochondrial cyclophilin D (gene PPIF, uniprot P30405) knockout mouse strain, result in offspring without this gender associated difference in the progression of the neurodegeneration. The authors show that in these crossed mice, cyclophilin D ablation increases Ca2+ load in mitochondria. Also, administering estradiol decreases Ca2+ load in G93A but has no effect on G93A/CypDKO mice. The authors propose that an estradiol bound estrogen receptor interacts with CypD, promoting controlled release of mitochondrial Ca2+ and preventing Ca2+ overload. This desensitizes mouse neurons to G93A-SOD1 induced oxidative stress and so inhibits PTP opening and apoptosis. This effect is greater in females who have higher endogenous estrogen levels explaining gender specific differences in susceptibility to ALS and other neurodegenerative diseases. In the future, this pathway may become a target for therapy in ALS and other chronic neurodegenerative diseases.


The mitochondrial calcium regulator cyclophilin D is an essential component of oestrogen-mediated neuroprotection in amyotrophic lateral sclerosis. Brain 2012. Kim HJ, Magranè J, Starkov AA, Manfredi G.


Also this month:

Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease. Antioxid Redox Signal. 2012. Thomas B, Banerjee R, Starkova NN, Zhang SF, Calingasan NY, Yang L, Wille E, Lorenzo BJ, Ho DJ, Beal MF, Starkov A.


Response to estradiol (17β-estradiol) may also be cell-type specific. This month Sastre-Serra et al. showed that two breast cancer cell lines, MCF7 and T47D, exhibit different responses to estradiol. MCF7 cells were shown to have higher levels of ER overall and interestingly, a higher ratio of α/β. Physiological concentrations of estradiol resulted in proliferation of both cell types. However MCF7 cells with higher ER α/β ratio show a decrease in mitochondrial OXPHOS protein complex expression, particularly in Complexes I and IV, and an associated decrease in several mitochondrial enzyme activities. This effect was not seen in estradiol treated T47D cells that have a low ER α/β ratio. The authors propose that metabolic changes occur in MCF7 cells due to changes in mitochondrial dynamics and also due to increased mitophagy. Presumably MCF7 cells have an increased rate of oxidative glycolysis to compensate for decreased mitochondrial function.


The ERα/ERβ ratio determines oxidative stress in breast cancer cell lines in response to 17β-estradiol.J Int Cell Biochem. 2012. Nadal-Serrano M, Sastre-Serra J, Pons DG, Miró AM, Oliver J, Roca P.


Mitochondrial dynamics is affected by 17β-estradiol in the MCF-7 breast cancer cell line. Effects on fusion and fission related genes.Int J Biochem Cell Biol 2012. Sastre-Serra J, Nadal-Serrano M, Pons DG, Roca P, Oliver J.


Also this month:


IGF binding protein-3 mediates stress-induced apoptosis in non-transformed mammary epithelial cells. J Cell Physiol 2012. Leibowitz BJ, Agostini-Dreyer A, Jetzt AE, Krumm CS, Cohick WS.


Preliminary evidences on mitochondrial injury and impaired oxidative metabolism in breast cancer. Mitochondrion 2012. Putignani L, Raffa S, Pescosolido R, Rizza T, Del Chierico F, Leone L, Aimati L, Signore F, Carrozzo R, Callea F, Torrisi MR, Grammatico P.

II. Interaction of beta-amyloid (Abeta) and mitochondria


Mitochondria are implicated in the etiologies of several other neurodegenerative diseases. In the case of Alzheimer's disease (AD) a clearer understanding of the connections between amyloid-beta toxicity, neurofibrillary tangles, and mitochondrial dysfunction in this disease pathophysiology is beginning to emerge.


Neurons have extensive processes that connect the bulbous soma with the synapses at the axon termini. Mitochondria must migrate from their sites of biogenesis in the soma to the distal portions of axons and dendrites, termed anterograde transport. Oxidative stress can result in protein aggregations that can lead to disruption of organelle migration along the microtubule tracks, blocked mitochondrial pores and induction of apoptosis.


This month three papers were published describing the interaction of Abeta with various mitochondrial membrane protein pore components using MitoSciences antibodies.


First, Amadoro et al. showed by co-immunoprecipitation and co-localization that the neurotoxic amino terminal form of tau protein and Abeta1-42 peptide interact with ANT and CypD of the permeability transition pore complex in mitochondria. Furthermore, tau and Abeta synergistically inhibit ANT activity in a competitive and a non-competitive manner, respectively, suggesting that mitochondrial dysfunction is triggered by ANT impairment.


Interaction between NH2-tau fragment and Aβ in Alzheimer's disease mitochondria contributes to the synaptic deterioration. Neurobiol Aging. 2012 Amadoro G, Corsetti V, Atlante A, Florenzano F, Capsoni S, Bussani R, Mercanti D, Calissano P.


In a second paper, Manczak and Reddy showed, by similar Co-immunoprecipitation means in both mouse and human disease samples, an interaction between these neurotoxic peptides, the mitochondrial outer membrane protein and a third putative permeability transition pore member, VDAC1.

Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer's disease. Human Mol Genetics 2012. Manczak M, Reddy PH.


Finally, Chen et al. this month showed that exposure of beta-amyloid precursor protein-expressing transgenic mice to the pesticide and mitochondrial complex I inhibitor, paraquat, resulted in increased H2O2, detection of protein markers of oxidative stress, reduced membrane potential and induced mitochondrial enzymatic dysfunction. The resulting mice showed an exacerbated AD phenotype and increased Abeta levels. Over-expression of the mitochondrial antioxidant enzyme Peroxiredoxin 3 abolished mitochondrial dysfunction and improved cognition with reduced Abeta levels. This shows that oxidative stress and mitochondrial dysfunction play a central part in the etiology of AD.


Cognitive impairment and increased Aβ levels induced by paraquat exposure are attenuated by enhanced removal of mitochondrial H2O2. Neurobiol Aging 2012. Chen L, Yoo SE, Na R, Liu Y, Ran Q.

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