Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are closely associated with
Type 2 diabetes mellitus (DM) is characterized by impaired insulin secretion from pancreatic
The mitochondrion is an intracellular double-membraned organelle found in most eukaryotic cells [
Insulin-resistant patients can develop overt type 2 DM when pancreatic
Roles of mitochondrial dysfunction in the pathogenesis of
Defective mitochondrial fatty acid metabolism in skeletal muscle is thought to affect insulin signaling pathways, thereby leading to insulin resistance [
The liver plays a crucial role in the development of insulin resistance and type 2 DM [
Adipose tissue has been described as an endocrine organ that plays a central role in fuel metabolism [
Many studies on rodents have shown that the capacity of mitochondria for oxidizing fatty acids in brown adipose tissue (BAT) plays a critical role in the regulation of adaptive thermogenesis, energy balance, and body weight [
The ER is a complex organelle that is found in all eukaryotic cells. Structurally, the ER is formed by an interconnected network of cisternae and microtubules. From a functional viewpoint, the ER plays a central role in protein folding and in quality control of newly synthesized proteins [
If proteins are to be folded properly within the ER, a balance must be struck between the ER protein load and ER folding capacity. A number of conditions can disrupt ER homeostasis, leading to accumulation of misfolded proteins within the lumen of the ER [
The UPR is triggered by three ER transmembrane proteins: protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). In unstressed conditions, ER luminal domain of these proteins are bound by the chaperone Bip, maintaining them in an inactive state until ER stress is present [
Activation of IRE1, which has endoribonuclease activity, leads to splicing of X-box binding protein-1 (XBP1) mRNA and translation of the active form (XBP1s) [
In response to ER stress, ATF6, released from Bip, translocates to the Golgi where it is cleaved by proteases into an active amino-terminal form [
ER stress plays an important role in the pathogenesis of type 2 DM, as such stress contributes to pancreatic
Several components of the UPR that contribute to
Roles of ER stress in the pathogenesis of
In addition to
A number of studies have shown structural communication between the mitochondria and the ER. The evidence includes cosedimentation of ER particles with mitochondria, as well as electron microscopic observation of a close physical apposition between mitochondria and the ER [
The structural membrane hat bridges between mitochondria and the ER is known as the mitochondria-associated membrane (MAM) [
Structural communication between mitochondria and the ER is also modulated by fission and fusion of mitochondria. Fission and fusion are regulated by a family of mitochondrion-shaping proteins including dynamin-related protein 1 (DRP1), mitofusin 1, and mitofusin 2 [
Mitochondrial dysfunction and ER stress have each been recognized to play crucial roles in the pathogenesis of type 2 DM. However, the individual stressors appear to act sequentially in various tissues. For example, accumulating evidence has shown that ER stress induces mitochondrial dysfunction, thereby leading to disruption of various physiological responses within cells [
Interactions between mitochondria and the ER facilitate control of Ca2+ signaling and Ca2+-dependent cellular processes such as apoptosis [
ROS are thought to act as local messengers between the ER and mitochondria [
Protein folding processes and the handling of Ca2+ within the ER each require large amounts of ATP. Accordingly, ATP depletion is one of the best-known mechanisms by which ER stress may be induced [
NO can bind to cytochrome c oxidase and inhibit the enzyme, in competition with oxygen [
Recently, we showed that impairment of mitochondrial function increases the levels of ER stress markers [
Mitochondrial dysfunction induces ER stress, and this, in turn, causes hepatic insulin resistance [
A number of events may contribute to the linking of mitochondrial dysfunction and ER stress. For example, local ATP pools in the mitochondria and the adjacent ER may be essential to supply the energy required by SERCA to import Ca2+ into the lumen of the ER. In agreement with this idea, inhibition of OXPHOS was shown to cause a prolonged delay in uptake of Ca2+ into the lumen of the ER; in addition, Ca2+ levels within the ER fell [
We have provided a brief overview of the interaction between mitochondrial dysfunction and ER stress. In particular, we examined the role played by such interaction in the pathogenesis of type 2 DM. Mitochondrial dysfunction and ER stress are essential for
Bidirectional communication between dysfunctional mitochondria and the ER under stress contributes to the development of type 2 DM.
This work was supported by the Korea Science and Engineering Foundation (KOSEF) grants funded by the Ministry of Science and Technology (2009-0091988), Seoul, Korea.