Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis

Abstract

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

Mfn2 is critical for brown adipose tissue thermogenic function

“…This could be due, at least in part, to a marked decrease in Complex I and III levels in the mitochondria from the BAT of Mfn2‐adKO animals, which dampened respiratory capacity in BAT homogenates. Mitochondrial dysfunction and reduced Complex I respiratory activity in Mfn2 defective tissues has been previously reported in conditional knockout models for POMC neurons and liver tissue (Sebastian et al , 2012; Schneeberger et al , 2013), albeit never as severe as in our Mfn2‐adKO mice. Decreased Complex I activity upon Mfn2 deficiency has also been observed in skeletal muscle, brain, and liver tissues (Sebastian et al , 2012; Schneeberger et al , 2013).…”

“…In line with this, Mfn2 deficiency has been shown to trigger ER stress at least in liver, brain, and muscle (Sebastian et al , 2012; Schneeberger et al , 2013). Confirming these observations, Mfn2 deficiency also increased ER stress markers and p‐IRE phosphorylation in BAT (Fig EV2E and F).…”

“…In mice, the whole‐body Mfn2 deficiency is lethal at mid‐gestation due to impairment of placental function (Chen et al , 2003). However, transgenic mice with tissue‐specific ablations of Mfn2 have unveiled the multiple metabolic roles of Mfn2 (Sebastian et al , 2012; Schneeberger et al , 2013). The liver‐specific deletion of Mfn2 led to systemic metabolic abnormalities, such glucose intolerance and enhanced hepatic gluconeogenesis (Sebastian et al , 2012).…”

“…However, transgenic mice with tissue‐specific ablations of Mfn2 have unveiled the multiple metabolic roles of Mfn2 (Sebastian et al , 2012; Schneeberger et al , 2013). The liver‐specific deletion of Mfn2 led to systemic metabolic abnormalities, such glucose intolerance and enhanced hepatic gluconeogenesis (Sebastian et al , 2012). In brain, POMC neuron‐specific deletion of Mfn2 induced hyperphagia and obesity while reducing energy expenditure (Schneeberger et al , 2013).…”

“…Many of these effects have been attributed to the ability of Mfn2 to mediate not only mitochondria–mitochondria contacts, but also to influence the interaction of mitochondria with other cellular membrane organelles. For example, Mfn2 has a critical role in the maintenance of mitochondria–endoplasmic reticulum (ER) interactions (de Brito & Scorrano, 2008; Cosson et al , 2012; Filadi et al , 2015), and ablation of Mfn2 triggered ER stress in virtually all models tested (Sebastian et al , 2012; Schneeberger et al , 2013). …”