Abstract
Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sites via what are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca2+ signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.
Highlights
Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia
A high glucose concentration can disrupt mitochondria-associated ER membranes (MAMs) integrity and reduce mitochondrial respiration through the phosphatase 2 alpha (PP2A) pathway [66]. These results indicate that MAM-mediated mitochondrial bioenergetics regulate insulin secretion but are in turn regulated by insulin signaling
Altered MAM integrity may lead to insulin resistance through the induction of endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and impaired metabolite synthesis and transport
Summary
Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia. MAMs play an important role in various cellular processes ranging from cell signaling and metabolite transport to cell death and survival [4] These cellular processes are partially involved in the insulin signaling pathway, and several proteins in this pathway, such as protein kinase B (PKB/AKT), mammalian target of rapamycin complex 2 (mTORC2) [5], and phosphatase and tensin homolog (PTEN) [6], can localize to MAMs and interact with MAM-resident proteins. This suggests that the MAM might serve as a key regulator of insulin signaling. We hypothesize that the MAM might be a promising therapeutic target for the treatment of T2DM
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
