In addition to driving gene transcription, some PPAR agonists interact directly with mitochondria (Colca et al., 2004; Geldenhuys et al., 2010). These effects can occur via mitoNEET, a protein in the mitochondrial outer membrane that is essential for maximal energy production (Wiley et al., 2007). Pioglitazone binds to mitoNEET and stabilizes its conformational structure (Colca et al., 2004; Paddock et al., 2007). The mitochondrial effects of pioglitazone likely extend to other PPAR agonists such as rosiglitazone, which also binds to mitoNEET (Geldenhuys et al., 2010; Bieganski and Yarmush, 2011). Given this novel direct mitochondrial target for PPAR agonists, work has focused on creating specific ligands for mitoNEET (Geldenhuys et al., 2010, 2011; Bieganski and Yarmush, 2011). These new ligands may prove effective at targeting mitochondrial dysfunction and improving recovery similar to traditional PPAR ligands.
