Toxicology Mechanisms and Methods, 14: 271–279, 2004 Copyright c  Taylor & Francis Inc. ISSN: 1537-6524 print / 1537-6516 online DOI: 10.1080/15376520490479620 Regulation of Mitochondrial Biogenesis in Eukaryotic Cells Anne Devin and Michel Rigoulet Institut de Biochimie et G´ en´ etique Cellulaires, UMR 5095 CNRS/Universit´ e Victor Segalen, 1 rue Camille Saint-Sa¨ ens, Bordeaux cedex 33077, France Mitochondria amount within a cell is modulated in response to energy demand. This involves a tight regulation of mitochondrial biogenesis and the coordinated expression of hundreds of genes, both at the nuclear and at the mitochondrial level. This review will focus on two aspects of mitochondrial biogenesis regulation: (i) In mammalian cells, physiological effectors, and the regulatory proteins that control the expression of the respiratory apparatus, will be considered, and different kinds of tissue will be addressed. (ii) In yeast, the regulation of mitochondrial biogenesis in response to growth conditions as well as the signaling pathway involved will be considered. Keywords Cyclic AMP/Ras, Mammalian, Protein Kinase, Yeast Mitochondria are intracellular organelles responsible for the generation of ATP from metabolic fuels through oxidative phos- phorylation. Strong reducing agents such as NADH and FADH2 donate electrons to the respiratory chain resulting in the estab- lishment of an electrochemical potential difference in protons across the mitochondrial inner membrane. This potential is in turn, used by the mitochondrial F0–F1 ATPsynthase, which cou- ples the proton input to ATP synthesis. These intracellular or- ganelles have to make energy conversion meet with energy de- mand, which can vary by consequential lengths. One can expect mitochondria to use at least two means, which are not exclu- sive, in order to do so. It is now well established that oxidative phosphorylations in the living cell are not functioning to their fullest (i.e., the maximal respiratory capacity is usually higher than the spontaneous respiratory rate), an increase in oxidative phosphorylation rate would thus allow an increase in energy conversion. Energy demand could also be met by a change in the amount of mitochondrial enzyme per cell, with a constant steady state in the activity of each compound. This latter seems to be the way favored by the eukaryotic cell in order to adjust energy production. Indeed, numerous papers now describe mod- Address correspondence to Michel Rigoulet, Institut de Biochimie et G´ en´ etique Cellulaires, UMR 5095 CNRS/Universit´ e Victor Segalen, 1 rue Camille Saint-Sa¨ ens, Bordeaux cedex 33077, France. E-mail: michel.rigoulet@ibgc.u-bordeaux2.fr ulations in the mitochondrial amount in response to modifica- tions in energy demand (Hood 2001 for review). The amount of mitochondria is often modulated in response to physiological conditions (i.e., muscle mitochondria proliferate in response to exercise training and electrical stimulation and thyroid hor- mones increase metabolic rate and mitochondrial enzyme levels in multiple tissues). Muscle mitochondria biogenesis is induced at the onset of differentiation as well. The proliferation of mi- tochondria also occurs in rodent’s brown fat during adaptative thermogenesis, which coincides with the activation and induc- tion of UCP-1 (Puigserver et al. 1998). One of the most important features of these organelles is that they have their own circular genome. In mammalian cells, the mitochondrial DNA contributes 13 mRNA, 22 tRNA, and 2 rRNA molecules that are essential for mitochondrial function. The thirteen mRNA molecules all encode components of the oxidative phosphorylation. Most of these thirteen components are combined with nuclear encoded proteins to form multisub- units holoenzymes like COX or respiratory chain complex 1. The function of these holoenzymes is clearly impaired if con- tribution from either genome is absent (Hoffbuhr et al. 2000). However, most of the proteins belonging to mitochondria are en- coded by the nuclear genome. Thus, mitochondrial biogenesis involves the coordinated expression of hundreds of genes both at the nuclear and at the mitochondrial level. The interaction between these two genomes, leading to functional mitochondria has gained some insights in the past few years. Depending on the physiological stimulus, various transcriptions factors/activators are activated for which recognition sequences on the promo- tor of various mitochondrial protein encoding genes have been shown. Moreover, mitochondrial phenotype can change. Indeed, mitochondrial content is commonly estimated by the change in maximal respiratory activity, of a typical marker enzyme like cit- rate synthase or by the change in content of a single protein like cytochrome c. This could be valid if one considers that mitochon- drial content is regulated as a whole (i.e., every single protein expression belonging to mitochondria is regulated in the same way). This assumption should be seriously reconsidered since it has been shown that mitochondrial protein composition can change in response to chronic exercise (Henriksson et al. 1986; Hood et al. 1992; Ornatsky et al. 1995; Takahashi et al. 1998). 271