**9. Abbreviations**

ANT, adenine nucleotide translocator; ATP, adenosine triphosphate; [Ca2+]cyt, cytosolic calcium-concentration; [Ca2+]er, endoplasmic reticulum calcium-concentration; [Ca2+]mt, mitochondrial calcium-concentration; Ca2+, calcium; DNA, Deoxyribonucleic acid, ETC, electron transport chain; ER, endoplasmic reticulum; Δψ, electrical potential; IMM, inner mitochondrial membrane; IP3, inositol 1,4,5-triphosphate; IP3R, inositol triphosphate receptor; MCU, mitochondrial Ca2+ uniporter; NCX/HCX, Na+/Ca2+ exchanger and H+/Ca2+ exchanger; OMM, outer mitochondrial membrane; OXPHOS, oxidative phosphorylation; PMCA, plasma membrane Ca2+-ATPase; SERCA, sarco-Endoplasmic reticulum Ca2+-ATPase; RYR, ryanodine receptor; SERCA, sarco-Endoplasmic reticulum Ca2+-ATPase; SOC, store operated channel.

#### **10. References**

50 Bioenergetics

parameter in healthy fibroblasts. Similar result was obtained recently in a study including a large number of patient fibroblasts with complex I deficiency (Willems et al., 2009). Also the reduced maximal [ATP] in the mitochondrial matrix and cytosol were fully normalized by CGP37157 treatment. The effect of CGP37157 was independent of the presence of extracellular Ca2+, excluding a stimulatory effect on Ca2+ entry across the plasma membrane

It is worth to mention that CGP37157 may also stimulate the IP3-induced release of Ca2+ from intracellular stores. In addition to these effects, CGP37157 was demonstrated to inhibit capacitative store refilling (Malli et al., 2005; Poburko et al., 2007). As far as its specificity is concerned, recent studies suggest that CGP37157 can also directly act on L-type Ca2+ channels (Thu le et al., 2006). Thus the use of this drug will hamper Ca2+-stimulated processes that depend on Ca2+ entry across the plasma membrane (Luciani et al., 2007). All over, these findings suggest that the mitochondrial Na+/Ca2+ exchanger is a potential target for drugs aiming to restore or improve Ca2+-stimulated mitochondrial ATP synthesis in OXPHOS deficiencies and highlight the role of Ca2+ deregulation in the development of

This literature analysis highlights the broad Ca2+ deregulation in different models of OXPHOS diseases and demonstrates the cross regulation between Ca2+ and bioenergetics in the development of mitochondrial and cellular pathologies. Some studies revealed also the potential use of Ca2+ modulating drugs to reveres mitochondrial pathology. These studies may encourage researcher to investigate systematically Ca2+ deregulation in OXPHOS and help to reveal new targets for the development of new or combined therapies to rescue

Work presented in this review has been supported by INSERM, CNRS, (AFM (11456 and 13291) and FRM (DEQ20071210550). We gratefully acknowledge INSERM for supporting the MD-PhD curriculum (Ecole de l'INSERM) of B. Oulès and the Italian Institute of

ANT, adenine nucleotide translocator; ATP, adenosine triphosphate; [Ca2+]cyt, cytosolic calcium-concentration; [Ca2+]er, endoplasmic reticulum calcium-concentration; [Ca2+]mt, mitochondrial calcium-concentration; Ca2+, calcium; DNA, Deoxyribonucleic acid, ETC, electron transport chain; ER, endoplasmic reticulum; Δψ, electrical potential; IMM, inner mitochondrial membrane; IP3, inositol 1,4,5-triphosphate; IP3R, inositol triphosphate receptor; MCU, mitochondrial Ca2+ uniporter; NCX/HCX, Na+/Ca2+ exchanger and H+/Ca2+ exchanger; OMM, outer mitochondrial membrane; OXPHOS, oxidative phosphorylation; PMCA, plasma membrane Ca2+-ATPase; SERCA, sarco-Endoplasmic reticulum Ca2+-ATPase; RYR, ryanodine receptor; SERCA, sarco-Endoplasmic reticulum

Technology, Genova, Italy for supporting the PhD curriculum of Dolores Del Prete.

mitochondrial and cellular pathology in OXPHOS diseases.

mitochondrial pathology in these diseases.

Ca2+-ATPase; SOC, store operated channel.

**8. Acknowledgements** 

**9. Abbreviations** 

(Willems et al., 2009).

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**1. Introduction** 

**3** 

**Bioenergetics Theory of Aging** 

The average lifespan of people in developed countries has tripled since ancient times while its maximum longevity (about 120 years) has remained invariable. The strategic goal of gerontology is to exceed this limit, i.e. to develop remedies which would allow the living of an indefinitely long life. However there have not been any significant advances in solving this problem so far. There is still no answer to even the fundamental question: what is the primary cause of degradation for all of an organism's functions (otherwise known as aging)? Actually, there are too many answers to this question: over 300 aging theories have been developed, and each of them provides a different response (Medvedev, 1990), although the majority of these theories now have only historical importance. Theories of aging are traditionally divided into two alternative groups. First, stochastic theories claim that there are no specific aging genes and that an organism's deterioration is the result of damaging factors. Second, and by way of contrast, programmed-aging theories assert that longevity is predetermined by a genetic program. Stochastic theories have dominated the discussion since gerontology became a branch of science, and the idea that aging is programmed has not yet received wide recognition, even though there is a lot of empirical evidence supporting it. There are several factors which impede the wide recognition of this idea. First, there is no evidence that longevity is under the control of natural selection; and second, there is no convincing mechanism the programmed of aging. Adherents of this view currently search for longevity genes in a practically blind or ad hoc fashion (Holzenberger et al., 2003; Kenyon, 2010). Many such genes have been found for various organisms, ranging from unicellular creatures to

mammals, but it is still unclear what processes they control (Anisimov, 2003).

versions of neuroendocrinal theories.

There are several different theories which are currently under consideration and which are based on reliable, proven evidence: i) the free radical theory which claims that aging is caused by an increased damage rate in cell structures due to an increased generation-rate of reactive oxygen species (ROS) by their own mitochondria; ii) the protein error theory which states that the primary cause is the age-dependent retardation of the protein synthesis rate; iii) the replicative senescence theory which argues that an age-dependent organism's senility is caused by the limitation of cell proliferation. There is also reliable evidence in support of other theories which are not as popular, for instance the immunological theory and several

Alexander G. Trubitsyn

*Vladivostok, Russia* 

*Institute of Biology and Soil Sciences,* 

 *Far East Division Russian Academy of Sciences,* 

