Mitochondria-associated endoplasmic reticulum membranes allow adaptation of mitochondrial metabolism to glucose availability in the liver

Abstract

Mitochondria-associated endoplasmic reticulum membranes (MAM) play a key role in mitochondrial dynamics and function and in hepatic insulin action. Whereas mitochondria are important regulators of energy metabolism, the nutritional regulation of MAM in the liver and its role in the adaptation of mitochondria physiology to nutrient availability are unknown. In this study, we found that the fasted to postprandial transition reduced the number of endoplasmic reticulum-mitochondria contact points in mouse liver. Screening of potential hormonal/metabolic signals revealed glucose as the main nutritional regulator of hepatic MAM integrity both in vitro and in vivo Glucose reduced organelle interactions through the pentose phosphate-protein phosphatase 2A (PP-PP2A) pathway, induced mitochondria fission, and impaired respiration. Blocking MAM reduction counteracted glucose-induced mitochondrial alterations. Furthermore, disruption of MAM integrity mimicked effects of glucose on mitochondria dynamics and function. This glucose-sensing system is deficient in the liver of insulin-resistant ob/ob and cyclophilin D-KO mice, both characterized by chronic disruption of MAM integrity, mitochondrial fission, and altered mitochondrial respiration. These data indicate that MAM contribute to the hepatic glucose-sensing system, allowing regulation of mitochondria dynamics and function during nutritional transition. Chronic disruption of MAM may participate in hepatic mitochondrial dysfunction associated with insulin resistance.

Metabolic signaling functions of ER–mitochondria contact sites: role in metabolic diseases

“…As the regulation of ER-mitochondria interaction by glucose levels allows to control mitochondria dynamics and function and was also suggested to adapt hepatic metabolism to nutritional state, chronic disruption of MAM could participate to both hepatic metabolic inflexibility and mitochondrial dysfunction associated with hepatic insulin resistance. In line with this evidence, ER-mitochondria interactions are controlled by PP2A (Theurey et al 2016), and hyperactivation of PP2A was associated with insulin resistance (Kowluru & Matti 2012). Therefore, increased PP2A activity could participate in the disruption of MAM in the liver of insulin-resistant mice.…”

“…In agreement, disruption of MAM inhibits starvation-induced autophagy by inhibiting the PS transfer from ER to mitochondria-derived autophagosomes (Hailey et al 2010), supporting the role of MAM in starvation-induced processes. Conversely, our laboratory further demonstrated that MAM integrity is reduced after feeding in liver, a regulation reproduced by increasing blood glucose levels (Theurey et al 2016). In agreement, high glucose levels reduced ER-mitochondria interactions and Ca 2+ exchange in HuH7 cells, pointing toward glucose as a major regulator of MAM integrity in high-energy state.…”

“…In agreement, high glucose levels reduced ER-mitochondria interactions and Ca 2+ exchange in HuH7 cells, pointing toward glucose as a major regulator of MAM integrity in high-energy state. At the molecular level, we revealed that high glucose levels disrupted MAM integrity and function through the pentose phosphate (PP)-PP2A pathway, and subsequently induced mitochondria fragmentation and altered mitochondria respiration (Theurey et al 2016). Altogether, these data point at MAM as a glucose sensor to adapt cellular bioenergetics, likely contributing to the adaptive fuel partitioning during nutritional transition.…”

“…Importantly, we found that chronic disruption of MAM in the liver of insulin-resistant mice is associated with a loss of MAM regulation by energy state. Indeed, fasting-to-postprandial transition reduced ER-mitochondria interactions in liver of wt mice, whereas this regulation is lost in the liver of obese and diabetic mice (Theurey et al 2016). Furthermore, sucrose consumption in drinking water also reduced ER-mitochondria interactions in liver of fasted wt mice, whereas this regulation is lost in the liver of ob/ob and CypD-KO mice, both characterized by chronic disruption of MAM integrity, mitochondrial fission and altered mitochondrial respiration.…”

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

“…A black background to the amino acid residue indicates identical residues, a red background to the amino acid residue indicates similar residues, and a yellow background divergent residues. metabolism and autophagy (Raturi and Simmen, 2013;Sood et al, 2014;Theurey et al, 2016). Mammalian MAMs are formed by protein tethers, similar to the tetrameric tethering complexes in fungi known as ER-mitochondria encounter structures (ERMES) (Kornmann et al, 2009).…”