bims-mecosi 2022-06-19 papers

Issue of 2022‒06‒19
three papers selected by
Verena Kohler

Biochimie. 2022 Jun 09. pii: S0300-9084(22)00165-1. [Epub ahead of print]

Stbd1-deficient mice display insulin resistance associated with enhanced hepatic ER-mitochondria contact.

Styliana Kyriakoudi, Andria Theodoulou, Louiza Potamiti, Fabian Schumacher, Margarita Zachariou, Revekka Papacharalambous, Burkhard Kleuser, Mihalis I Panayiotidis, Anthi Drousiotou, Petros P Petrou.

Starch binding domain-containing protein 1 (STBD1) is an endoplasmic reticulum (ER)-resident, glycogen-binding protein. In addition to glycogen, STBD1 has been shown to interact with several proteins implicated in glycogen synthesis and degradation, yet its function in glycogen metabolism remains largely unknown. In addition to the bulk of the ER, STBD1 has been reported to localize at regions of physical contact between mitochondria and the ER, known as Mitochondria-ER Contact sites (MERCs). Given the emerging correlation between distortions in the integrity of hepatic MERCs and insulin resistance, our study aimed to delineate the role of STBD1 in vivo by addressing potential abnormalities in glucose metabolism and ER-mitochondria communication associated with insulin resistance in mice with targeted inactivation of Stbd1 (Stbd1KO). We show that Stbd1KO mice at the age of 24 weeks displayed reduced hepatic glycogen content and aberrant control of glucose homeostasis, compatible with insulin resistance. In line with the above, Stbd1-deficient mice presented with increased fasting blood glucose and insulin levels, attenuated activation of insulin signaling in the liver and skeletal muscle and elevated liver sphingomyelin content, in the absence of hepatic steatosis. Furthermore, Stbd1KO mice were found to exhibit enhanced ER-mitochondria association and increased mitochondrial fragmentation in the liver. Nevertheless, the enzymatic activity of hepatic respiratory chain complexes and ER stress levels in the liver were not altered. Our findings identify a novel important role for STBD1 in the control of glucose metabolism, associated with the integrity of hepatic MERCs.

Keywords: Glycogen; Insulin resistance; Mice; Mitochondria-ER contact Sites; Mitochondrial fragmentation; STBD1

DOI: https://doi.org/10.1016/j.biochi.2022.06.003

Front Cell Dev Biol. 2022 ;10 915931

Targeting ER-Mitochondria Signaling as a Therapeutic Target for Frontotemporal Dementia and Related Amyotrophic Lateral Sclerosis.

Sandra M Martín-Guerrero, Andrea Markovinovic, Gábor M Mórotz, Shaakir Salam, Wendy Noble, Christopher C J Miller.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two major neurodegenerative diseases. FTD is the second most common cause of dementia and ALS is the most common form of motor neuron disease. These diseases are now known to be linked. There are no cures or effective treatments for FTD or ALS and so new targets for therapeutic intervention are required but this is hampered by the large number of physiological processes that are damaged in FTD/ALS. Many of these damaged functions are now known to be regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by "tethering" proteins that serve to recruit ER to mitochondria. One tether strongly associated with FTD/ALS involves an interaction between the ER protein VAPB and the mitochondrial protein PTPIP51. Recent studies have shown that ER-mitochondria signaling is damaged in FTD/ALS and that this involves breaking of the VAPB-PTPIP51 tethers. Correcting disrupted tethering may therefore correct many other downstream damaged features of FTD/ALS. Here, we review progress on this topic with particular emphasis on targeting of the VAPB-PTPIP51 tethers as a new drug target.

Keywords: ER-mitochondria contact; amyotrophic lateral sclerosis (ALS); endoplasmic reticulum; frontotemporal dementia (FTD); mitochondria; therapeutic targets

DOI: https://doi.org/10.3389/fcell.2022.915931

Am J Physiol Cell Physiol. 2022 Jun 15.

Mitofusin 2 positively regulates Ca2+ signaling by tethering the sarcoplasmic reticulum and mitochondria in rat aortic smooth muscle cells.

Sou Inagaki, Yoshiaki Suzuki, Keisuke Kawasaki, Rubii Kondo, Yuji Imaizumi, Hisao Yamamura.

Mitochondria buffer cytosolic Ca2+increases following Ca2+ influx from extracellular spaces and Ca2+ release from intracellular Ca2+ store sites under physiological circumstances. Therefore, close contact of mitochondria with the sarcoplasmic reticulum (SR) is required for maintaining Ca2+ homeostasis. Mitofusin 2 (Mfn2) localizes in both mitochondrial and SR membranes, and is hypothesized to optimize the distance and Ca2+ transfer between these organelles. However, the physiological significance of Mfn2 in vascular smooth muscle cells (VSMCs) is poorly understood. In the present study, the role of Mfn2 in the physical and functional couplings between SR and mitochondria was examined in rat aortic smooth muscle cells (rASMCs) by confocal and electron microscope imaging. When Mfn2 was knocked-down using siRNA in rASMCs, the mean distance between these organelles was extended from 16.2 to 21.6 nm. The increase in the cytosolic Ca2+ concentration ([Ca2+]cyt) induced by 100 nM arginine vasopressin (AVP) was not affected by Mfn2 siRNA knockdown, whereas cytosolic Ca2+ removal was slower after Mfn2 knockdown. Following the AVP-induced [Ca2+]cyt increase, mitochondrial Ca2+ uptake and Ca2+ refill into the SR were attenuated by Mfn2 knockdown. In addition, Mfn2-knockdown cells exhibited a loss of mitochondrial membrane potential (ΔΨmito) and lower ATP levels in mitochondria. Moreover, Mfn2 knockdown inhibited cell proliferation. In contrast, Mfn2 overexpression increased ΔΨmito and cell growth. This study strongly suggests that Mfn2 is responsible for SR-mitochondria Ca2+ signaling by tethering mitochondria to SR, thereby regulating ATP production and proliferation of VSMCs.

Keywords: calcium; mitochondria; mitofusin; sarcoplasmic reticulum; smooth muscle

DOI: https://doi.org/10.1152/ajpcell.00274.2021