Cardiac contraction requires a high and reliable flux of ATP as energetic deficiencies lead to disease, as seen in humans with mutations in mitochondrial DNA or nuclear-encoded respiratory genes. This is supported by mouse models with mutations in genes of oxidative metabolism. Cardiac energy metabolism and, in particular, the high capacity for ATP production are controlled by a network of transcriptional regulators, including the coactivators PGC-1? and PGC-1?, and the orphan nuclear receptors ERR? and ERR?. This network regulates genes important for mitochondrial biogenesis, oxidative metabolism and thus contraction of cardiac myocytes (CM). PGC-1/ ERR complexes act directly on many target genes, but also activate downstream transcription factors that amplify and/or extend their scope of action. Elucidation of such PGC-1/ERR downstream effectors can reveal novel molecules that impact heart bioenergetics and that could be used to beneficially modify cardiac energy state. Here, we will elucidate the role of a novel gene, PERM1, in cardiac energy metabolism. We identified it as a gene induced by PGC-1?/? and ERR?/?/????and found it expressed specifically in tissues with high-energy demand, such as heart and skeletal muscle, and induced in vivo by signals known to activate PGC-1?. We hypothesize that PERM1 acts with PGC-1 and ERR factors in controlling the expression of genes important for mitochondrial biogenesis and ATP production, thereby protecting the heart from heart failure induced by pressure overload and ischemia reperfusion injury. Three aims will test this hypothesis: Aim 1. Study of the metabolic pathways regulated by Perm1 in cardiomyocytes (CM). This aim will study metabolic pathways regulated by Perm1 in cultured CM to evaluate the hypothesis that Perm1 modulates Mito biogenesis and cellular metabolic pathways in the CM. It will pursue the involvement of PGC-1/ERR in Perm1 function, and also evaluate mechanism(s) by which Perm1 modulates PGC-1/ERR activity using directed and unbiased approaches, including metabolomics. Aim 2. Determine the role of Perm1 in pressure overload-induced HF. We will focus on the role of Perm1 in the heart subjected to hemodynamic stress, and assess its role as the heart undergoes evolution from compensated hypertrophy to HF. For this we use mouse models (in hand) which direct CM-specific overexpression and ablation (knockout (KO)) of Perm1 expression ? (termed Perm1cTg and Perm1cKO, respectively). Aim 3. Evaluate the role of Perm1 in providing cardiac protection from deleterious effects of ischemia and ischemia-reperfusion (IR) injury. We will study the role of Perm1 in ischemic injury also using our unique mouse models, given the hypothesis that Perm1cTG-mediated overexpression will be cardioprotective in the ischemic heart, while Perm1cKO will produce deleterious responses in ischemic- challenged hearts. We expect this work to define PERM1 as a regulator of cellular bioenergetics and potentially provide a new target for therapeutic pathways that are applicable to treatment of heart failure.