5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 8–11 July 2003, Le Meridien Montparnasse, Paris, France

MITOCHONDRIAL METABOLISM, ENERGY HOMEOSTASIS AND CELL DEATH

Antiviral Therapy 2003; 8:L3 (abstract P5)

X Leverve
Département de Médecine Aiguë Spécialisée, Unité de Nutrition Parentérale, Hôpital Albert Michallon, Grenoble CEDEX 9; and INSERM-E-0221 Bioénergétique Fondamentale et Appliquée, Université J. Fourier, Grenoble CEDEX 9, France

Mitochondria are mostly viewed as specialized cellular micro-organelles in charge of energetic supply by for ATP synthesis via the oxidative phosphorylation pathway. This function is indeed prominent in living organisms, and defect in mitochondrial metabolism is accompanied by dramatic consequence at the level of cellular, or whole body, energy metabolism. Lactate metabolism plays a key role in the overall energy homeostasis and it is often simply viewed as being: (i) responsible for metabolic acidosis, which is; (ii) related to anoxia or ischaemia; and (iii) associated with poor prognosis. Actually, if lactate metabolism is connected to anaerobic glycolysis, lactate is an excellent oxidizable substrate, since it can be easily converted to pyruvate and thus oxidized, transaminated or involved in gluconeogenesis. Moreover, glycolytic-related ATP synthesis is a major pathway in several cell types such as erythrocytes and white blood cells, but probably also endothelial cells, kidney tubules, etc. Hence, the main question is to understand the metabolic meaning of alteration in its turnover. Several recent experimental works have shown that instead of being a negative consequence, the stimulation of lactate turnover could be a protective adapted response.

In addition, due to the specific features of mitochondrial respiratory chain: formation of single unpaired electron leading to reactive oxygen species (ROS), mitochondrial metabolism is potentially extremely harmful. Therefore, there is a strong requirement of adjustment between energy demand and energy supply, and respiratory chain is tightly controlled. Mitochondria are in the centre of a complicated cell sensing/signalling system, and extended works during the last decade have greatly contributed to emphasize its central role in the regulation of several main cellular functions, including the control of cell death. The mechanism relating mitochondria and cell death still requires some clarification, but it is probable that the mitochondrial permeability transition pore (PTP) is involved via the release of cytochrome in the cytosol, which activates the caspase cascade. It is suggested that complex 1 plays a central role in the control of oxidative phosphorylation, ROS production and in the commitment to cellular death. Mild inhibition of complex 1 has been shown to interfere with ROS-related cell death.

Presenting author: X Leverve

2003-07-08
P5

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