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Departamento de Biología Molecular Centro de Biología Molecular "Severo Ochoa" UAM-CSIC, Facultad de Ciencias, Universidad Autónoma, Madrid; and Área de Bioquímica, Centro Regional de Investigaciones Biomédicas (CRIB), Facultad de Ciencias del Medio Ambiente, Universidad de Castilla-La Mancha, Toledo, Spain
Ca2+ signaling in mitochondria is important to tune mitochondrial function to a variety of extracellular stimuli. The main mechanism is Ca2+ entry in mitochondria via the Ca2+ uniporter followed by Ca2+ activation of three dehydrogenases in the mitochondrial matrix. This results in increases in mitochondrial NADH/NAD ratios and ATP levels and increased substrate uptake by mitochondria. We review evidence gathered more than 20 years ago and recent work indicating that substrate uptake, mitochondrial NADH/NAD ratios, and ATP levels may be also activated in response to cytosolic Ca2+ signals via a mechanism that does not require the entry of Ca2+ in mitochondria, a mechanism depending on the activity of Ca2+-dependent mitochondrial carriers (CaMC). CaMCs fall into two groups, the aspartate-glutamate carriers (AGC) and the ATP-Mg/Pi carriers, also named SCaMC (for short CaMC). The two mammalian AGCs, aralar and citrin, are members of the malate-aspartate NADH shuttle, and citrin, the liver AGC, is also a member of the urea cycle. Both types of CaMCs are activated by Ca2+ in the intermembrane space and function together with the Ca2+ uniporter in decoding the Ca2+ signal into a mitochondrial response.
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