A mathematical model is developed to analyze the influence of chemical reaction and diffusion processes on the intracellular organization of mitochondria in skeletal muscle cells. The mathematical modeling approach uses a reaction-diffusion analysis of oxygen, ATP, and ADP involved in energy metabolism and mitochondrial function as governed by oxygen supply, volume fraction of mitochondria, and rates of reaction. Superimposed upon and coupled to the continuum species material balances is a cellular automata (CA) approach governing mitochondrial life cycles in response to the metabolic state of the cell. The effectiveness factor (eta), defined as the ratio of reaction rate in the system with finite rates of diffusion to those in the absence of any diffusion limitation is used to assess diffusional constraints in muscle cells. The model shows the dramatic effects that the governing parameters have on the mitochondrial cycle of life and death and how these effects lead to changes in the distribution patterns of mitochondria observed experimentally. The model results showed good agreement with experimental results on mitochondrial distributions in mammalian muscle fibers. The eta increases as the mitochondrial population is redistributed toward the fiber periphery in response to a decreased availability of oxygen. Modification of the CA parameters so that the mitochondrial lifecycle is more sensitive to the oxygen concentration caused larger mitochondrial shifts to the edge of the cell with smaller changes in oxygen concentration, and thus also lead to increased values of eta. The present study shows that variation in oxygen supply, muscle activity and mitochondrial ATP supply influence the eta and are the important parameters that can cause diffusion limitations. In order to prevent diffusion constraints, the cell resorts to shifts in their mitochondrial population towards the cell periphery, thus increasing eta. Biotechnol. Bioeng. 2011;108: 1912-1924. (C) 2011 Wiley Periodicals, Inc.