Mitochondrial Physiology Network 10.9: 27 (2005) - download pdf

The effect of hypoxia upon the expression pattern of isoforms and the kinetics of cytochrome c oxidase in astrocytes and neurons.

S Härtig, Susanne Arnold

Emmy Noether Research Group 'Brain Energy Metabolism', Cellular Neurosciences, Max Delbrueck Center for Molecular Medicine, Robert-Roessle-Str. 10, 13092 Berlin, Germany. - arnold@mdc-berlin.de

    The brain is the organ with the highest energy demand in mammalian organisms. Neurons and astrocytes, two different brain cell types, are structurally, functionally, and metabolically tightly coupled with astrocytes playing a central role in regulation of cerebral energy metabolism in dependence on neuronal activity. Oxygen is, besides glucose, the most important substrate to fulfil neuronal energetic requirements and also the substrate of cytochrome c oxidase (COX), the enzyme that is engaged in mitochondrial oxidative energy metabolism. Mammalian COX is composed of three catalytic, mitochondrially encoded and ten regulatory, nuclear encoded subunits. The regulatory COX subunit IV plays an important role in adjusting energy production to energetic requirements by binding of ATP to the N-terminus of subunit IV and thereby causing an allosteric inhibition of COX activity at high energy level, i.e. high ATP/ADP ratio [1]. It was found that this COX subunit is expressed in isoforms (IV-1 and IV-2). While isoform IV-1 is ubiquitously transcribed in all adult mammalian tissues including brain, isoform IV-2 showed so far high transcription levels only in the lung [2]. 

    Besides the expression of COX IV-1 isoform in astrocytes and neurons from mouse and rat brains, we detected also mRNA transcripts for the COX IV-2 isoform in neurons pointing at a cell type specific expression of COX subunit IV isoforms in the brain. Under conditions of oxygen deprivation mRNA transcription of COX IV-2 is induced in astrocytes and upregulated in neurons. So far, yeast has been the only organism known to express two isoforms (Va and Vb), homologous to the mammalian subunit IV, in dependence on oxygen concentration [3]. The functional consequences of an increased expression of COX IV-2 isoform, that structurally differs from COX IV-1 isoform in its N-terminus, are reflected in the abolition of allosteric inhibition of COX by ATP at high ATP/ADP levels. We conclude that the expression of COX IV-2 isoform under hypoxia suppresses the sensitivity of COX to its allosteric regulator ATP and overrules the regulation of COX by the cellular energy level. 

     Supported by Deutsche Forschungsgemeinschaft (Emmy Noether-Program to SA).

1.  Arnold S, Kadenbach B (1999) The intramitochondrial ATP/ADP-ratio controls cytochrome c oxidase activity allosterically. FEBS Lett. 443: 105-108.

2.  Hüttemann M, Kadenbach B, Grossman LI (2001) Mammalian subunit IV isoforms of cytochrome c oxidase. Gene 267: 111-123.

3.  Allen LA, Zhao XJ, Caughey W, Poyton RO (1995) Isoforms of yeast cytochrome c oxidase subunit V affect the binuclear reaction center and alter the kinetics of interaction with the isoforms of yeast cytochrome c. J. Biol. Chem. 270: 110-118.