Aerobic metabolism depends on the capacity of mitochondria to generate ATP at rates

mitochondria to generate ATP at rates sufficient to meet the energetic demands of tissues. Metabolic regulation of enzymes allows cells to use the existing pool of mitochondria to match energy production to energy demand, even under rapidly changing conditions. Cells can regulate energetics by altering the structural architecture of mitochondria, such as the dynamics of the mitochondrial reticulum (Bach et al., 2003). The efficiency of the mitochondrial metabolism can also be altered, without inducing global changes in mitochondrial structure or enzymology (Harper and HimmsHagen, 2002). For example, changes in the magnitude of the proton leak can influence the amount of energy used by mitochondria to maintain the proton motive force, an important contribution to resting metabolic rate (Cadenas et al., 2001). When changes in energy demands persist for long periods, most cells can respond by modifying the rates of mitochondrial biogenesis to induce compensatory changes in mitochondrial capacity. Modulation of muscle mitochondrial content begins early in embryonic development, when muscle precursors differentiate and diverge to form distinct fiber types. Muscle mitochondrial content remains plastic throughout adulthood, increasing in response to hypermetabolic conditions, or decreasing with periods of reduced activity. Mitochondrial content of homologous muscles varies widely between species in relation to body size and activity levels. Taking into consideration the entire scope of variation between tissues and species, mitochondrial content varies by at least two orders of magnitude among vertebrate muscles (Fig.·1). The scope of this variation can be attributed to muscle specializations, allometric scaling, and inter-species differences in activity levels. Recent studies in control of gene expression have provided insight into how mitochondria are built and how their levels are altered during development and in response to environmental cues (reviewed in Moyes and Hood, 2003). Comparative biochemists, physiologists and cell biologists can use this information to identify targets that might contribute to evolutionary variation. The process of building, maintaining and modifying muscle mitochondria is very complex. Global changes in mitochondrial content require exquisite coordination of hundreds of different genes located in the nucleus, in parallel with the genes encoded by mitochondrial DNA (mtDNA). Synthesis of the appropriate amounts of mitochondrial proteins also requires coordination of protein synthesis in both the cytoplasm and mitochondria. Furthermore, most enzymes within mitochondria change, more or less, in parallel to maintain enzyme ratios or stoichiometries. For example, mitochondrial content differs almost tenfold between red and white muscles of fish, yet the ratios of mitochondrial enzymes are nearly identical (Leary et al., 2003). How are complex pathways altered, while retaining intrinsic stoichiometries in enzyme levels? 4385 The Journal of Experimental Biology 206, 4385-4391 © 2003 The Company of Biologists Ltd doi:10.1242/jeb.00699