Its effects on mitochondria can be reversed by treatment with losartan. These results suggest that TNF-a plays a relevant role in decreasing eNOS expression and mitochondrial biogenesis in metabolically active LV tissues of TNF treated animals. Mitochondrial permeability transition pores are multiprotein complexes consisting of the adenine nucleotide translocase, voltage dependent anion channel, cytochrome C, cyclophilin D, and several other ancillary proteins. The exact components that constitute the MPTP remain a subject of debate, although it is generally accepted that ANT and cytochrome C are major pore components. Increased oxidative stress can inhibit cytochrome c by increasing mitochondrial ROS production. The redox state of the respiratory complexes is a major determinant of mitochondrial ROS production and is highest when the mitochondrial complexes are highly reduced. In the present study, we demonstrate that chronic TNF treatment induces MPTP pore opening and causes mitochondrial swelling due to osmotic water entry, expansion of the inner membrane and consequent rupture of the outer membrane. As a consequence, MPTP proteins, such as ANT and cytochrome c, are released, and there is depletion of the activities of electron transport complexes I, II, and III and ANT due to the outermembrane rupture. Treatment with losartan reduced mitochondrial damage and restored mitochondrial complex activity and prevented cardiac dysfunction. Cardiac function is an energy driven process. In this study, we measured mitochondrial genes in the LV in TNF treated rats using real time RT-PCR. PGC1a is a coactivator of nuclear transcription factors, including PPARc, PPARa, and nuclear respiratory factor 1 and these genes are known to enhance mitochondrial activity. PGC-1a is abundantly expressed in the heart, and is known to 1) activate most genes of mitochondrial function and biogenesis, and 2) stimulate both fatty acid oxidation and oxidative respiration in cardiac tissue.In the present study, we have demonstrated that decreased expression of the PGC-1 gene caused significant deficiencies in cardiac energy reserves and function. Moreover, mitochondrial protein levels, PGC-1a PGC -1b, CPT1, CPT 2 and UCP 3 were decreased in parallel, as were ATP production, thereby playing an important role in mitochondrial biogenesis. Thus, it is believed that abnormalities in mitochondrial biogenesis, mitochondrial number, and mitochondrial function contribute to altered energy metabolism, leading to cardiac dysfunction. Changes in mitochondrial morphology were also observed in tissues from TNF-treated rats. This study suggests that, in the presence of an inflammatory condition, mitochondrial biogenesis and mitochondrial fatty acid oxidation are negatively altered and contribute to altered energy metabolism, leading to cardiac dysfunction in the rat. Our data demonstrates that LOS treatment attenuates oxidative stress and can increase mitochondrial function directly, through MG132 up-regulation of electron transport chain activities, or indirectly, through a decrease in free radical generation, thereby restoring cardiac function. Taken together, these results demonstrate the presence of functionally significant interactions between RAS and TNF in the heart and suggest an mportant role for these interactions in the development of cardiac disease in this model.