L15

MITOCHONDRIAL CA2+ HOMEOSTASIS AND THE CONTROL OF ENERGY METABOLISM IN NORMAL AND DISEASED CELLS

Rosario Rizzuto, Paolo Pinton, Marisa Brini, L. Sophie Jouaville, Luisa Filippin, Anna Chiesa and Tullio Pozzan

Dept. of Exp. Diagn. Medicine, Section of General Pathology, University of Ferrara, via Borsari 46, 44100 Ferrara, Italy.

Although it has been known for over three decades that [Ca2+] regulates three dehydrogenases of the Krebs cycle, until a few years ago mitochondria were believed to play a marginal role in calcium homeostasis. Indeed, the low affinity of the mitochondrial Ca2+ transporters led to the consensus that, in physiological conditions, Ca2+ uptake into mitochondria would be marginal. In the past years, by measuring specifically the [Ca2+] in the mitochondria, cytosol and ER with targeted chimeras of the Ca2+-sensitive photoprotein aequorin, we have shown that this is not the case. When Ca2+ is released from the ER (or enters through plasma membrane channels), mitochondria, located in the proximity of the open channels, sense microdomains of high [Ca2+], that meet the affinity of the uptake systems and allow large and rapid increases in mitochondrial Ca2+ concentration ([Ca2+]m), sufficient to stimulate the Ca2+-sensitive dehydrogenases. Thus, as directly shown by monitoring NADH fluorescence and ATP levels (with a targeted chimera of the ATP-sensitive photoprotein luciferase), mitochondrial Ca2+ signalling allows to tune mitochondrial activity to the increased metabolic needs of a stimulated cell. This local signalling route, that strongly depends on close contacts of the mitochondria with the Ca2+ sources and on the driving force for accumulation provided by the mitochondrial membrane potential, are specifically affected in mtDNA-inherited oxidative phosphorylation defects.

References. 
Rizzuto et al. Science 280, 1763-1766, 1998.
Brini et al., Nat. Med. 5, 951-954, 1999.