Tretter 2013 Abstract MiP2013

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Tretter L, Komlódi T, Ádám-Vizi V (2013) The effects of methylmalonic acid on alpha-ketoglutarate supported oxidation in isolated brain, heart and liver mitochondria. Mitochondr Physiol Network 18.08.

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MiP2013, Book of Abstracts Open Access

Tretter L, Komlodi T, Adam-Vizi V (2013)

Event: MiPNet18.08_MiP2013

Methylmalonic acid (Mma) is a common intermediate in many catabolic processes. Its accumulation is associated with neurological symptoms. In methylmalonic acidemia mitochondrial dysfunction can be observed. In this study the effects of Mma were tested in isolated brain, heart and liver mitochondria. Oxygen consumption of isolated mitochondria was measured by Clark electrode, ATP synthesis was estimated by coupled enzyme assay, mitochondrial membrane potential was measured by safranin fluorescence. It was found that in the presence of Mma alpha-ketoglutarate (aKG) oxidation was significantly increased in isolated mitochondria. The oxidation of Mma is reflected in the increased ATP production and membrane hyperpolarization. This phenomenon could be explained by: (i) The mitochondrial transport of aKG was increased by Mma; (ii) The added Mma was itself activated and oxidized; (iii) alpha-ketoglutarate dehydrogenase (aKGDH) activity was increased by Mma. The effect of Mma on isolated aKGDH was tested and found that the enzyme activity was inhibited by Mma. Our results are in good agreement with that of Melo et al (2012). According to their interpretation the stimulating effect of Mma can be attributed to the stimulation of aKG transport. Our recent experiments however showed that this stimulation does not occur in liver mitochondria but it is pronounced in mitochondria isolated from the brain and heart, respectively. One of the differences between these types of mitochondria is that heart and brain are tissues able to oxidize ketone bodies. We interpret our results that a reaction analogous to the ketone body activation may activate methylmalonate to methylmalonyl-CoA. This reaction occurs in the heart and brain, but not in the liver mitochondria, respectively. This hypothesis is supported by the Mma-induced changes in P/O ratio. In brain and heart mitochondria in the presence of Mma, P/O ratio of aKG oxidation decreases. This finding is in agreement with the hypothesis that acetoacetate:succinyl-CoA transferase can transfer CoA and activates Mma to Mma-CoA.

Keywords: Methylmalonic acid, Safranine

O2k-Network Lab: HU Budapest Tretter L


Labels: MiParea: Respiration, Comparative MiP;environmental MiP  Pathology: Neurodegenerative 

Organism: Guinea pig  Tissue;cell: Heart, Nervous system, Liver  Preparation: Isolated mitochondria 

Regulation: ATP, Coupling efficiency;uncoupling, Inhibitor, mt-Membrane potential 

Pathway:HRR: Oxygraph-2k 

alpha-ketoglutarate, MiP2013 

Affiliations and author contributions

Semmelweis University, Dept of Medical Biochemistry and Hungarian Academy of Science, Laboratory for Neurobiochemistry and Molecular Physiology, Budapest, Hungary. - Email: [email protected]


Supported by OTKA (NK 81983), TAMOP (4.2.2./B-09/1), MTA (MTA TKI 2006 TKI88) to V.A-V.