Mitochondria are dynamic organelles that play a key role in energy conversion. Optimal mitochondrial function is ensured by a quality-control system tightly coupled to fusion and fission. In this connection, mitofusin 2 (Mfn2) participates in mitochondrial fusion and undergoes repression in muscle from obese or type 2 diabetic patients. Here, we provide in vivo evidence that Mfn2 plays an essential role in metabolic homeostasis. Liver-specific ablation of Mfn2 in mice led to numerous metabolic abnormalities, characterized by glucose intolerance and enhanced hepatic gluconeogenesis. Mfn2 deficiency impaired insulin signaling in liver and muscle. Furthermore, Mfn2 deficiency was associated with endoplasmic reticulum stress, enhanced hydrogen peroxide concentration, altered reactive oxygen species handling, and active JNK. Chemical chaperones or the antioxidant N-acetylcysteine ameliorated glucose tolerance and insulin signaling in liver-specific Mfn2 KO mice. This study provides an important description of a unique unexpected role of Mfn2 coordinating mitochondria and endoplasmic reticulum function, leading to modulation of insulin signaling and glucose homeostasis in vivo.mitochondrial dynamics | insulin resistance | metabolism | oxidative stress

There were errors published in J. Cell Sci. 124, 2143Sci. 124, -2152 In the section given below, PtdIns(3,4,5)P 3 was on four occasions incorrectly printed instead of the correct Ins(1,4,5)P 3 .We apologise for this mistake. Increased mitochondrial Ca2+ drives the adaptive metabolic boost observed during early phases of ER stress Increases in mitochondrial respiration and ATP production are often consequences of increases in mitochondrial Ca 2+ (Green and Wang, 2010). In order to determine whether early phases of ER stress induced by tunicamycin increased mitochondrial Ca 2+ , we treated cells expressing cytosolic or mitochondrial aequorins with histamine [which evokes Ins(1,4,5)P 3 -dependent Ca2+ release] and compared their mitochondrial Ca 2+ uptake. We observed that histamine led to a mitochondrial Ca 2+ uptake that was significantly higher in tunicamycinpretreated cells (P<0.05; 4 hours) than in untreated cells (Fig. 6A). Cytosolic Ca 2+ increased similarly in tunicamycin-treated and untreated cells (Fig. 6B). These results indicate that the differences in mitochondrial Ca 2+ levels are not due to altered Ca 2+ release mediated by the Ins(1,4,5)P 3 receptor but to an enhanced mitochondrial Ca 2+ uptake, presumably due to the increased apposition of ER and mitochondrial Ca 2+ channels. By using a different dye, Fura-2, we monitored the peak cytosolic Ca 2+ levels after thapsigargin addition, reflecting the kinetics of Ca 2+ release after sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) inhibition. After 4 hours of tunicamycin treatment, the thapsigargin-induced Ca 2+ peak was increased, and it was further elevated by inhibition of mitochondrial Ca 2+ uptake using Ru360 (Fig. 6C). These results suggest that, besides the Ins(1,4,5)P 3 -receptor-mediated direct Ca 2+ transfer from the ER to neighboring mitochondria, an additional phenomenon associated with the early phases of ER stress involves Ca 2+ leak from the ER, also resulting in mitochondrial Ca 2+ uptake. Indeed, no mitochondrial Ca 2+ uptake following the thapsigargin-induced Ca 2+ leak was observed in Mfn2-knockout cells (Fig. 6D), which is reflected by the lack of effect of Ru360. This result further indicates that juxtaposition of mitochondria with the ER is necessary for the mitochondrial Ca 2+ uptake evoked by Ca 2+ leak during early phases of ER stress.Finally, to test whether mitochondrial Ca 2+ levels control the metabolic mitochondrial boost, we measured oxygen consumption rates resulting from OXPHOS in the presence of the Ins(1,4,5)P 3 receptor inhibitor xestospongin B or the mitochondrial Ca 2+ uptake inhibitor RuRed. We observed that both xestospongin B and RuRed decreased the rate of oxygen consumption after tunicamycin treatment (Fig. 7A,B), which confirms that increased mitochondrial Ca 2+ uptake, resulting from ER-mitochondrial coupling, is necessary for the metabolic response observed during early phases of ER stress. Therefore, in order to evaluate whether the early metabolic boost forms part of an adaptive response triggere...