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Mitochondrial permeability transition

January, 2012

Edited by James Murray, PhD.

Past issues are available for review in the archives.

Thousands of researchers around the world are studying the connection between mitochondria, metabolism and disease.  In MitoNews we will summarize a selection of the latest published findings and highlight how MitoSciences & Abcam research tools have contributed to this effort.  The full list of 62 original research papers published this month using MitoSciences’ products can be found here.   

Table of Contents

I. Oxidative stress-the mitochondrial PTP and CyclophilinD 

II. Mitochondrial genetic disease

III.  Cancer – metabolism and mitochondria

IV. Neurodegeneration – Bioenergetics and Complex I

V.  Drug Toxicity and mitochondria


I. Oxidative stress -the mitochondrial PTP and CyclophilinD

Cellular oxidative stress and high calcium concentrations are triggers for mitochondrial permeability transition leading to cell death by mitochondrial swelling and rupture.  This process is implicated in ischemia, reperfusion injury and in excitotoxicity. The transition requires the formation of the Cyclosporin A sensitive mitochondrial permeability transition pore (MPTP).  The components of the pore are currently unknown but may include, or at least is regulated by, Cyclophilin D (CypD, gene PPIF).  Cyp D is the binding site for Cyclosporin A and PPIF knockout mice are insensitive to Ca2+ induced permeability transition.

Four research papers this month used MitoSciences’ Cyclophilin D antibody (ab110324) to show under different pro-oxidative and anti-oxidative conditions regulation of the levels of CypD and hence the MPTP.

Greco, Shafer and Fiskum demonstrated that exposure of rats to sulfopraphane, an activator of the Nrf2 pathway, led to an increase in anti-oxidant enzymes but not CypD nor mitochondrial porin.  The treatment desensitized the MPTP under several conditions of oxidative stress.  The improved antioxidative capacity may increase redox buffering and removal of oxidants while maintaining PTP-associate protein sulfhydryls in a reduced state.

Sulforaphane inhibits mitochondrial permeability transition and oxidative stress.    Greco T, Shafer J, Fiskum G.

A critical sulfhydryl may be C203 of CypD.  Nguyen and colleagues prepared a CypD knockout and expressed a C203S mutant in mouse embryonic fibroblasts confirmed by CypD Western blotting.  Unlike the WT protein the mutant C203S CypD did not induce MPTP opening under conditions of oxidative stress.  Similarly, in mice C203S CypD were less sensitive to Ca2+ induced MPTP opening.  These results suggest that C203 may form a redox sensitive disulfide bond critical for MPTP opening.

Cysteine 203 of cyclophilin D is critical for cyclophilin D activation of the mitochondrial permeability transition pore.    Nguyen TT, Stevens MV, Kohr M, Steenbergen C, Sack MN, Murphy E.


In a pig model of hypercholesterolemia by McCommis and colleagues, MPTP sensitivity was enhanced in the myocardium.  Paradoxically, a significant decrease in CypD, other putative MPTP components and several anti-oxidant enzymes were also observed by Western blotting when compared to control proteins such as cytochrome-c oxidase subunit II.  One possible explanation proposed is that hypercholesterolemia induces increased oxidative stress, which compromises anti-oxidant enzymes and increases the sensitivity of the MPTP.  The cellular response to increased sensitivity is to reduce the components of the MPTP.  Intriguingly, exercise was able to normalize the MPTP response and return enzymes and CypD to normal levels - not by reducing cholesterol levels but by improving the functioning of mitochondria alone.

Hypercholesterolemia increases mitochondrial oxidative stress and enhances the MPT response in the porcine myocardium: beneficial effects of chronic exercise.    McCommis KS, McGee AM, Laughlin MH, Bowles DK, Baines CP.

Other CypD/MPTP related literature this month:

Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons.    Sterky FH, Hoffman AF, Milenkovic D, Bao B, Paganelli A, Edgar D, Wibom R, Lupica CR, Olson L, Larsson NG.

The cyclophilin inhibitor alisporivir prevents hepatitis C virus- mediated mitochondrial dysfunction.    Quarato G, D'Aprile A, Gavillet B, Vuagniaux G, Moradpour D, Capitanio N, Piccoli C.

II. Mitochondrial genetic disease

Two reports validated MitoSciences’ OXPHOS activity dipstick assays in the evaluation of samples from patients with mitochondrial genetic disease.  Importantly, both studies used minimally invasive buccal swab sample collection.  These samples were compared favorably with muscle biopsy when using these dipstick tests for Complex I and IV activity.

Non-invasive evaluation of buccal respiratory chain enzyme dysfunction in mitochondrial disease: Comparison with studies in muscle biopsy.    Goldenthal MJ, Kuruvilla T, Damle S, Salganicoff L, Sheth S, Shah N, Marks H, Khurana D, Valencia I, Legido A.

Buccal Swab Analysis of Mitochondrial Enzyme Deficiency and DNA Defects in a Child With Suspected Myoclonic Epilepsy and Ragged Red Fibers (MERRF).    Yorns WR Jr, Valencia I, Jayaraman A, Sheth S, Legido A, Goldenthal MJ.

III.  Cancer – metabolism and mitochondria

Ye et al. showed that the Ski oncogene shifted the metabolism of chicken embryo fibroblasts from glycolytic to increased mitochondrial function, in contrast to the alteration of fibroblast metabolism by other oncogenes.  The mechanism by which this may occur seems to involve Ski-induced activation of PPARγ resulting in increased oxidative metabolism in general and specifically mitochondrial beta oxidation.  Increases in the following proteins were shown by Western blot; NDUFS3, 70-kDa Fp, PDH E1α, complex III subunit core1, and porin.

Peroxisome proliferator-activated receptor γ) (PPARγ) mediates a Ski oncogene-induced shift from glycolysis to oxidative energy metabolism.    Ye F, Lemieux H, Hoppel CL, Hanson RW, Hakimi P, Croniger CM, Puchowicz M, Anderson VE, Fujioka H, Stavnezer E.


Researchers Sun, Board and Blackburn targeted two metabolic processes up-regulated in cancer cells, mitochondrial glutaminolysis and aerobic glycolysis, with inhibitors arsenic trioxide (ATO) and dichloroacetate (DCA), respectively.  The effects of these treatments on the proliferation of cultured breast cancer cells were additive and measured using the PDH activity assay and a series of antibodies from MitoSciences and Abcam (HIF-1α, Bcl-2, ATP synthase β-subunit and β-actin).

Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells.     Sun RC, Board PG, Blackburn AC.


Tello et al. identified the product of the complex I gene NDUFA4L2 as a target in the Hif pathway which leads to reduced Complex I activity, Complex IV, mitochondrial membrane potential, and oxygen consumption.

Induction of the Mitochondrial NDUFA4L2 Protein by HIF-1α Decreases Oxygen Consumption by Inhibiting Complex I Activity.    Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordóñez A, Corral-Escariz M, Soro I, López-Bernardo E, Perales-Clemente E, Martínez-Ruiz A, Enríquez JA, Aragonés J, Cadenas S, Landázuri MO.

IV. Neurodegeneration – Bioenergetics and Complex I

Lee et al. demonstrated that another environmental toxin, fluzinam, is toxic to dopaminergic neurons and acts by inhibiting Complex I activity, generates ROS and triggers cell death via the intrinsic model of apoptosis.

Fluazinam-induced apoptosis of SH-SY5Y cells is mediated by p53 and Bcl-2 family proteins.    Lee JE, Kang JS, Shin IC, Lee SJ, Hyun DH, Lee KS, Koh HC.

Sterky et al. strengthened the case between Parkinson’s disease and Complex I dysfunction by loss of NUDFS4 in a knockout model.
Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons.    Sterky FH, Hoffman AF, Milenkovic D, Bao B, Paganelli A, Edgar D, Wibom R, Lupica CR, Olson L, Larsson NG. 

V.  Drug Toxicity and mitochondria
Long term treatment with NRTI has revealed cardiotoxicity by mitochondrial inhibition.  Liu et al confirmed that extended exposure of rat cardiomycotes to NTRIs (AZT, AZT+ddI) significantly affected mitochondrial biogenesis using MitoSciences’ mitobiogenesis in-cell ELISA assay.

Molecular Analysis of Mitochondrial Compromise in Rodent Cardiomyocytes Exposed Long Term to Nucleoside Reverse Transcriptase Inhibitors (NRTIs).    Liu Y, Nguyen P, Baris TZ, Poirier MC.

New Products This Month:



OTC Protein

Biogenesis WB Cocktail

ECH1 Antibody

PCB Antibody


CTIP2 Antibody FITC

Featured Products:

 Monoclonal Antibodies:

Cyclophilin D

(MSA04, ab110324)

OXPHOS Human WB Antibody Cocktail

(MS601, ab110411)

OXPHOS Rodent WB Antibody Cocktail

(MS604, ab110413)

Enzyme Activity Assay Kits:

Complex I Activity Dipstick Kit (MS130, ab109720)

Complex IV Activity Dipstick  (MS430, ab109786)

Complex I Activity Microplate (MS141, ab109721)

Complex IV Activity Microplate (MS441, ab109909)

Protein Quantity Assay Kits:

HIf1a ELISA (ab117996)

PDH E1a ELISA (ab115342)

Phospho S232 PDH E1a ELISA (ab115343)

Phospho S293 PDH E1a ELISA (ab115344)

Phospho S300 PDH E1a ELISA (ab115345)


In Cell ELISA Kits:

MitoBiogenesis™ In-Cell ELISA Kit (IR) (MS642, ab110216)


Copyright (C) 2012 MitoSciences Inc. All rights reserved. 

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