cKO mice die within 6 days of birth. Although the cause of death in MFN2 deficient animals is uncertain, they are underweight, lack milk spots and exhibit an unsteady gait. A similar phenotype has been described in mice lacking MFN2 in the cerebellum and, as the Pax2 promoter selected in the present study is also expressed in the mid- and hind-brain, extra-renal loop-out of the MFN2f allele in the central nervous system is get PTK/ZK likely the cause of the early death in our mice. Although Pax2-Cre+/ MFN2f/+ mice survived and exhibited intermediate body weight, highly variable mitochondrial morphology was observed, precluding further studies in Pax2-Cre+/MFN2f/+ mice or cells harvested from their kidneys. As a result, our in vivo model of MFN2deficiency is limited as we are unable to analyze the role of MFN2 in mature collecting duct cells that is only seen in three to four week old mice. We are therefore unable to study the susceptibility of MFN2 cKO to acute or chronic kidney disease. The small blood volume collected from four-day old pups also precludes measurement of creatinine, a second estimate of GFR that could confirm our BUN data. We recognize that MFN1 and MFN2 may have partially redundant functions and while the marked fragmentation 5 January 2012 | Volume 7 | Issue 1 | e31074 MFN2 in Renal Stress observed in MFN2-deficient cells both in vivo and in vitro may suggest that MFN2 is the major mediator of mitochondrial fusion in renal epithelial cells, we have not addressed the role of MFN1 in our studies. The kidney is somewhat unique in that it operates in a relatively hypoxic environment and is therefore remarkably susceptible to ischemic injury. Mitochondrial fragmentation and fusion are recently reported to be involved in both acute and chronic cellular stress responses in the kidney. Renal ischemia-reperfusion injury in vivo causes a marked shift from filamentous to fragmented mitochondria and mice treated with a Drp1 inhibitor, which prevents fragmentation, are protected from ischemia- injury. Similarly, MFN2 over-expression that promoted “2987739 mitochondrial fusion has been suggested to delay the onset of chronic diabetic nephropathy in mice. In keeping with these in vivo data, Hela cells over-expressing MFN1 or MFN2, as well as rat proximal tubule cells expressing dominant negative Drp1, have filamentous mitochondria and are protected from azide or cisplatin-induced apoptosis. In contrast, Mouse embryonic fibroblasts from MFN1 or 2 knockout mice have increased mitochondrial fragmentation and are more prone to injury-induced cell death. In the kidney, we show that mouse proximal tubule cells, a primary target of acute and chronic renal injury, are more susceptible to metabolic stress when MFN2 expression is reduced and mitochondria fragmented. MFN2-deficiency did not affect cell survival at baseline or mitochondrial energetics but markedly increases the leakage of both cytochrome c and AIF from the outer mitochondrial membrane following ATP depletion, demonstrating that MFN2 plays an important role in protecting renal tubule cells from stress-induced apoptosis. Our data suggest that targeting mitochondrial dynamics may be an important therapeutic option to ameliorate tubular cell death following acute or chronic renal insults. How fission and fusion mediate susceptibility to renal cell death is presently “2987731 unclear. Given that BCL proteins regulate mitochondrial injury during in vitro metabolic stress and following ischemia-reperfusion inju