The regulation of OXPHOS by extramitochondrial calcium.
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.
Gellerich
Frank N
FN
KeyNeurotek Pharmaceuticals AG, ZENIT Technology Park, Leipziger Str. 44, D-39120 Magdeburg, Germany. frank.gellerich@keyneurotek.de
Gizatullina
Zemfira
Z
Trumbeckaite
Sonata
S
Nguyen
Huu P
HP
Pallas
Thilo
T
Arandarcikaite
Odeta
O
Vielhaber
Stephan
S
Seppet
Enn
E
Striggow
Frank
F
D000818:Animals; D017920:Antiporters / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005993:Glycerolphosphate Dehydrogenase / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D008954:Models, Biological; D010085:Oxidative Phosphorylation; D010088:Oxidoreductases / Q000378:metabolism; D010101:Oxygen Consumption; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
C086357:ATP-Mg-Pi carrier proteins, mitochondria; D017920:Antiporters; D015220:Calcium Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D050994:Voltage-Dependent Anion Channels; C034703:mitochondrial calcium uniporter; D018698:Glutamic Acid; D010088:Oxidoreductases; D005993:Glycerolphosphate Dehydrogenase; C471850:glycerol-3-phosphate dehydrogenase, FAD-dependent; D003576:Electron Transport Complex IV; D025261:Mitochondrial Proton-Translocating ATPases; D002118:Calcium