Ups (unprocessed) proteins are putative lipid carriers that were identified in yeast and are homologous with the mammalian MSF1/PRELI protein families ( Sesaki et al., 2006). In eukaryotes, CL biosynthesis requires that its substrate PA is trafficked to the matrix side of the IM ( Schlame and Haldar, 1993). The unique dimeric phospholipid CL is specific to mitochondrial and bacterial membranes. The role of the Ups family of proteins (Ups1-3p) in mitochondrial phospholipid metabolism has been investigated and evidence supports their involvement in both PE and CL synthesis ( Osman et al., 2009 Potting et al., 2010 Tamura et al., 2009). Lipid carriers may also be involved in shuttling incoming PS to the IM although a potential PS carrier has not been identified. Whether transport of PS between OM and IM leaflets utilizes MICOS-based IM/OM scaffolds has yet to be elucidated. MICOS is a hetero-oligomeric protein complex that is conserved from yeast to mammals and is important for mitochondrial biogenesis, morphology, and inheritance. Akin to the numerous tethers between the outer membrane and other organelles, there is an IM/OM scaffold termed the mitochondrial contact site and cristae organizing system (MICOS) this scaffold is also crucial for cristae junction formation ( Alkhaja et al., 2012 Harner et al., 2011 Hoppins et al., 2011 Itoh et al., 2013 Jans et al., 2013 von der Malsburg et al., 2011). Similarly, PS import from the OM to the IM in yeast is ATP-independent and does not require either a functional membrane potential or oxidative phosphorylation machinery ( Achleitner et al., 1995, 1999 Gnamusch et al., 1992). Since both compounds are uncouplers that disrupt oxidative phosphorylation, this suggests that dinitrophenol impairs PS uptake by either disturbing IM/OM contacts or increasing the distance between these two membranes ( Knoll and Brdiczka, 1983). In mammals, dinitrophenol but not carbonyl cyanide m-chlorophenyl hydrazone inhibits PS import from the OM to the IM ( Hovius et al., 1992). Claypool, in International Review of Cell and Molecular Biology, 2016 3.2.3.2 Within Mitochondria