Hax1 plays an important role in immunodeficiency syndromes and apoptosis. Recently, Chao et al., (Nature, 2008) reported that Hax1 is a Bcl-2-family-related protein required to suppress apoptosis in lymphocytes and neurons via a mechanism that involves association to the rhomboid protease PARL in the mitochondria intermembrane space (IMS). Mechanistically, Hax1/PARL interaction allows the recruitment of the serine protease Omi/HtrA2 and its presentation to PARL, which cleaves it to generate a form of Omi/HtrA2 that may proteolytically eliminate active Bax during mitochondrial outer membrane permeabilization (MOMP). The results of this study imply that the control of cell-type sensitivity to proapoptotic stimuli is governed by the PARL/Hax1 complex in the IMS and, more generally, that Bcl-2-family-related proteins can control MOMP from the inside of the mitochondrion. Further, it defines a novel, antiapoptotic Opa1-independent pathway for PARL. Here we present evidence that Hax1 is not a Bcl-2-family-related protein. Also, that in vivo the activity of Hax1 cannot be mechanistically coupled to PARL because the two proteins are confined in distinct cellular compartments and their interaction in vitro is an artifact. Our results indicate a different function and mechanism of Hax1 in apoptosis and re-opens the question of whether mammalian PARL, in addition to apoptosis, regulates mitochondrial stress response through Omi/HtrA2 processing.