The Control of Brain Mitochondrial Energization by Cytosolic Calcium: The Mitochondrial Gas Pedal

IUBMB Life. 2013 Mar;65(3):180-90. doi: 10.1002/iub.1131. Epub 2013 Feb 8.


This review focuses on problems of the intracellular regulation of mitochondrial function in the brain via the (i) supply of mitochondria with ADP by means of ADP shuttles and channels and (ii) the Ca(2+) control of mitochondrial substrate supply. The permeability of the mitochondrial outer membrane for adenine nucleotides is low. Therefore rate dependent concentration gradients exist between the mitochondrial intermembrane space and the cytosol. The existence of dynamic ADP gradients is an important precondition for the functioning of ADP shuttles, for example CrP-shuttle. Cr at mM concentrations instead of ADP diffuses from the cytosol through the porin pores into the intermembrane space. The CrP-shuttle isoenzymes work in different directions which requires different metabolite concentrations mainly caused by dynamic ADP compartmentation. The ADP shuttle mechanisms alone cannot explain the load dependent changes in mitochondrial energization, and a complete model of mitochondrial regulation have to account the Ca(2+) -dependent substrate supply too. According to the old paradigmatic view, Ca(2+) (cyt) taken up by the mitochondrial Ca(2+) uniporter activates dehydrogenases within the matrix. However, recently it was found that Ca(2+) (cyt) at low nM concentrations exclusively activates the state 3 respiration via aralar, the mitochondrial glutamate/aspartate carrier. At higher Ca(2+) (cyt) (> 500 nM), brain mitochondria take up Ca(2+) for activation of substrate oxidation rates. Since brain mitochondrial pyruvate oxidation is only slightly influenced by Ca(2+) (cyt) , it was proposed that the cytosolic formation of pyruvate from its precursors is tightly controlled by the Ca(2+) dependent malate/aspartate shuttle. At low (50-100 nM) Ca(2+) (cyt) the pyruvate formation is suppressed, providing a substrate limitation control in neurons. This so called "gas pedal" mechanism explains why the energy metabolism of neurons in the nucleus suprachiasmaticus could be down-regulated at night but activated at day as a basis for the circadian changes in Ca(2+) (cyt) . It also could explain the energetic disadvantages caused by altered Ca(2+) (cyt) at mitochondrial diseases and neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Amino Acid Transport Systems, Acidic / metabolism
  • Antiporters / metabolism
  • Aspartic Acid / metabolism
  • Calcium / metabolism*
  • Circadian Rhythm / physiology
  • Cytosol / metabolism
  • Energy Metabolism
  • Feedback, Physiological*
  • Humans
  • Intracellular Membranes / metabolism
  • Malates / metabolism
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Neurons / metabolism
  • Oxidative Phosphorylation
  • Pyruvic Acid / metabolism
  • Suprachiasmatic Nucleus / metabolism*


  • Amino Acid Transport Systems, Acidic
  • Antiporters
  • Malates
  • Mitochondrial Membrane Transport Proteins
  • aspartate-glutamate carrier
  • Aspartic Acid
  • Adenosine Diphosphate
  • malic acid
  • Pyruvic Acid
  • Calcium