The regulation of OXPHOS by extramitochondrial calcium

Abstract

Despite extensive research, the regulation of mitochondrial function is still not understood completely. Ample evidence shows that cytosolic Ca2+ has a strategic task in co-ordinating the cellular work load and the regeneration of ATP by mitochondria. Currently, the paradigmatic view is that Cacyt2+ taken up by the Ca2+ uniporter activates the matrix enzymes pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and isocitrate dehydrogenase. However, we have recently found that Ca2+ regulates the glutamate-dependent state 3 respiration by the supply of glutamate to mitochondria via aralar, a mitochondrial glutamate/aspartate carrier. Since this activation is not affected by ruthenium red, glutamate transport into mitochondria is controlled exclusively by extramitochondrial Ca2+. Therefore, this discovery shows that besides intramitochondrial also extramitochondrial Ca2+ regulates oxidative phosphorylation. This new mechanism acts as a mitochondrial "gas pedal", supplying the OXPHOS with substrate on demand. These results are in line with recent findings of Satrustegui and Palmieri showing that aralar as part of the malate-aspartate shuttle is involved in the Ca2+-dependent transport of reducing hydrogen equivalents (from NADH) into mitochondria. This review summarises results and evidence as well as hypothetical interpretations of data supporting the view that at the surface of mitochondria different regulatory Ca2+-binding sites exist and can contribute to cellular energy homeostasis. Moreover, on the basis of our own data, we propose that these surface Ca2+-binding sites may act as targets for neurotoxic proteins such as mutated huntingtin and others. The binding of these proteins to Ca2+-binding sites can impair the regulation by Ca2+, causing energetic depression and neurodegeneration.

Activity-dependent Increases in Local Oxygen Consumption Correlate with Postsynaptic Currents in the Mouse CerebellumIn Vivo

“…Thus, neurons could match or possibly anticipate the ATP consumption of ion pumps by using cytosolic Ca 2ϩ elevations to increase mitochondrial respiration (Gunter et al, 2004). Recently, a study of isolated brain mitochondria suggested that brain ATP production and thus CMRO 2 are controlled by a feedforward mechanism exclusively involving non-mitochondrial Ca 2ϩ (Gellerich et al, 2010). Furthermore, in isolated PCs in vitro, increased cytosolic Ca 2ϩ evoked by high extracellular K ϩ induced both mitochondrial depolarization due to mitochondrial Ca 2ϩ entry via the uniporter and an immediate burst in O 2 consumption (Hayakawa et al, 2005).…”

“…In addition, respiration is controlled by the Ca 2ϩ -dependent mitochondrial aspartate-glutamate transporter, which increases mitochondrial nicotinamide adenine dinucleotide (NADH) levels (Satrú stegui et al, 2007). Indeed, recent studies suggest that glutamate-dependent oxidative phosphorylation in mitochondria is exclusively triggered by extramitochondrial Ca 2ϩ in physiological concentration ranges (Gellerich et al, 2010). Furthermore, rapid rises in oxygen consumption mediated by increased cytosolic Ca 2ϩ concentrations have been demonstrated in cultured Purkinje cells (PCs) (Hayakawa et al, 2005).…”

Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

“…To confirm that Ca 2ϩ can influence AGC1 activity in rodent retinas we isolated mitochondria from rat retinas and measured their O 2 consumption over a range of free Ca 2ϩ concentrations using either glutamate and malate (Glu/Mal) or pyruvate and malate (Pyr/Mal) as fuel in a buffer containing EGTA. Oxidation of the Glu/Mal mix depends on AGC activity, whereas oxidation of the Pyr/Mal mix occurs independently of AGC1 (67). A, ADP was added at time 0 on this graph followed at 5 min (short dashed line) by either Pyr/Mal (black) or Glu/Mal (red) and then 20-nmol stepwise additions of CaCl 2 (longer dashed lines).…”

The low doses effect of experimental zearalenone (ZEN) intoxication on the presence of Ca2+ in selected ovarian cells from pre-pubertal bitches

“…The mitochondria produce ATP as a result of oxidative phosphorylation, they regulate intracellular Ca 2+ homeostasis and the production of reactive oxygen species (ROS) (Gellerich et al 2010, Moreira et al 2011. The mitochondria also play a key role in apoptotic processes (Moreira et al 2011).…”