Extramitochondrial Ca2+ in the nanomolar range regulates glutamate-dependent oxidative phosphorylation on demand.
We present unexpected and novel results revealing that glutamate-dependent oxidative phosphorylation (OXPHOS) of brain mitochondria is exclusively and efficiently activated by extramitochondrial Ca(2+) in physiological concentration ranges (S(0.5) = 360 nM Ca(2+)). This regulation was not affected by RR, an inhibitor of the mitochondrial Ca(2+) uniporter. Active respiration is regulated by glutamate supply to mitochondria via aralar, a mitochondrial glutamate/aspartate carrier with regulatory Ca(2+)-binding sites in the mitochondrial intermembrane space providing full access to cytosolic Ca(2+). At micromolar concentrations, Ca(2+) can also enter the intramitochondrial matrix and activate specific dehydrogenases. However, the latter mechanism is less efficient than extramitochondrial Ca(2+) regulation of respiration/OXPHOS via aralar. These results imply a new mode of glutamate-dependent OXPHOS regulation as a demand-driven regulation of mitochondrial function. This regulation involves the mitochondrial glutamate/aspartate carrier aralar which controls mitochondrial substrate supply according to the level of extramitochondrial Ca(2+).
Gellerich
Frank Norbert
FN
KeyNeurotek Pharmaceuticals AG, ZENIT Technology Park, Magdeburg, Germany. frank.gellerich@keyneurotek.de
Gizatullina
Zemfira
Z
Arandarcikaite
Odeta
O
Jerzembek
Doreen
D
Vielhaber
Stefan
S
Seppet
Enn
E
Striggow
Frank
F
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012430:Ruthenium Red / Q000378:metabolism
D012430:Ruthenium Red; D018698:Glutamic Acid; D000244:Adenosine Diphosphate; D002118:Calcium