bims-mecosi 2022-03-27 papers

Issue of 2022–03–27
seven papers selected by
Verena Kohler, Stockholm University

Biochem Pharmacol. 2022 Mar 18. pii: S0006-2952(22)00105-8. [Epub ahead of print] 115011

Potential role of mitochondria-associated endoplasmic reticulum membrane proteins in diseases.

Hui Mao, Wei Chen, Linxi Chen, Lanfang Li.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic membrane coupling regions formed by the coupling of the mitochondrial outer membrane and endoplasmic reticulum (ER). MAMs are involved in the mitochondrial dynamics, mitophagy, Ca2+ exchange, and ER stress. A large number of studies indicate that many proteins are involved in the formation of MAMs, including dynamic-related protein 1 (Drp1), DJ-1, PTEN-induced putative kinase 1 (PINK), α-synuclein (α-syn), sigma-1 receptor (S1R), mitofusin-2 (Mfn2), presenilin-1 (PS1), protein kinase R (PKR)-like ER kinase (PERK), Parkin, Cyclophilin D (CypD), glucose-related protein 75 (Grp75), FUN14 domain containing 1 (Fundc1), vesicle-associated membrane-protein-associated protein B (VAPB), phosphofurin acidic cluster sorting protein 2 (PACS-2), ER oxidoreductin 1 (Ero1), and receptor expression-enhancing protein 1 (REEP1). These proteins play an important role in the structure and functions of the MAMs. Abnormalities in these MAM proteins further contribute to the occurrence and development of related diseases, such as neurodegenerative diseases, non-alcoholicfattyliverdisease (NALFD), type 2 diabetes mellitus (T2DM), and diabetic kidney (DN). In this review, we introduce important proteins involved in the structure and the functions of the MAMs. Furthermore, we effectively summarize major insights about these proteins that are involved in the physiopathology of several diseases through the effect on MAMs.

Keywords: Mitochondria-associated endoplasmic reticulum membranes; diabetic kidney; neurodegenerative diseases; non-alcoholic fatty liver disease; type 2 diabetes mellitus

DOI: https://doi.org/10.1016/j.bcp.2022.115011

STAR Protoc. 2022 Jun 17. 3(2): 101262

Live cell microscopy of mitochondria-lysosome contact site formation and tethering dynamics.

Tayler B Belton, Eric D Leisten, Jasmine Cisneros, Yvette C Wong.

Mitochondria-lysosome contact sites are critical for maintaining cellular homeostasis by regulating mitochondrial and lysosomal network dynamics and mediating metabolite exchange. Here, we present a protocol to quantitatively analyze the formation and tethering duration of mitochondria-lysosome contact sites by using time-lapse live confocal microscopy of LAMP1 and TOMM20. Although this protocol focuses on mammalian HeLa cells, it can be applied to other cell types for further studies on mitochondria-lysosome contact regulation and function, and elucidation of their role in human disorders. For complete details on the use and execution of this protocol, please refer to Wong et al. (2018) and Wong et al. (2019b).

Keywords: Cell Biology; Cell culture; Microscopy

DOI: https://doi.org/10.1016/j.xpro.2022.101262

Biomolecules. 2022 Feb 23. pii: 352. [Epub ahead of print]12(3):

The Role of Lipids in CRAC Channel Function.

Lena Maltan, Ana-Marija Andova, Isabella Derler.

The composition and dynamics of the lipid membrane define the physical properties of the bilayer and consequently affect the function of the incorporated membrane transporters, which also applies for the prominent Ca2+ release-activated Ca2+ ion channel (CRAC). This channel is activated by receptor-induced Ca2+ store depletion of the endoplasmic reticulum (ER) and consists of two transmembrane proteins, STIM1 and Orai1. STIM1 is anchored in the ER membrane and senses changes in the ER luminal Ca2+ concentration. Orai1 is the Ca2+-selective, pore-forming CRAC channel component located in the plasma membrane (PM). Ca2+ store-depletion of the ER triggers activation of STIM1 proteins, which subsequently leads to a conformational change and oligomerization of STIM1 and its coupling to as well as activation of Orai1 channels at the ER-PM contact sites. Although STIM1 and Orai1 are sufficient for CRAC channel activation, their efficient activation and deactivation is fine-tuned by a variety of lipids and lipid- and/or ER-PM junction-dependent accessory proteins. The underlying mechanisms for lipid-mediated CRAC channel modulation as well as the still open questions, are presented in this review.

Keywords: CRAC channel; ER-PM junctions; Orai1; STIM1; lipids; modulatory proteins; protein-lipid interactions

DOI: https://doi.org/10.3390/biom12030352

Biomolecules. 2022 Mar 10. pii: 427. [Epub ahead of print]12(3):

Nuclear-Mitochondrial Interactions.

Brittni R Walker, Carlos T Moraes.

Mitochondria, the cell's major energy producers, also act as signaling hubs, interacting with other organelles both directly and indirectly. Despite having its own circular genome, the majority of mitochondrial proteins are encoded by nuclear DNA. To respond to changes in cell physiology, the mitochondria must send signals to the nucleus, which can, in turn, upregulate gene expression to alter metabolism or initiate a stress response. This is known as retrograde signaling. A variety of stimuli and pathways fall under the retrograde signaling umbrella. Mitochondrial dysfunction has already been shown to have severe implications for human health. Disruption of retrograde signaling, whether directly associated with mitochondrial dysfunction or cellular environmental changes, may also contribute to pathological deficits. In this review, we discuss known signaling pathways between the mitochondria and the nucleus, examine the possibility of direct contacts, and identify pathological consequences of an altered relationship.

Keywords: MAMs; integrated stress response; mitochondria; nucleus; retrograde signaling

DOI: https://doi.org/10.3390/biom12030427

Curr Opin Cell Biol. 2022 Mar 17. pii: S0955-0674(22)00017-5. [Epub ahead of print]75 102070

Seipin collaborates with the ER membrane to control the sites of lipid droplet formation.

Roger Schneiter, Vineet Choudhary.

Most cells store metabolic energy in lipid droplets (LDs). LDs are composed of a hydrophobic core, covered by a phospholipid monolayer, and functionalized by a specific set of proteins. Formation of LDs takes place in the endoplasmic reticulum (ER), where neutral lipid biosynthetic enzymes are located. Recent evidence indicate that this process is confined to specific ER subdomains, where proteins meet to initiate LD assembly. The lipodystrophy protein Seipin, is emerging as a major coordinator of LD biogenesis. Seipin forms a large oligomeric toroidal structure, which traps neutral lipids to promote LD nucleation. Here, we discuss the role of LD biogenesis factors that associate with Seipin to assemble functional LDs.

DOI: https://doi.org/10.1016/j.ceb.2022.02.004

Front Cell Dev Biol. 2022 ;10 832887

Podocyte Injury in Diabetic Kidney Disease: A Focus on Mitochondrial Dysfunction.

Simeng Liu, Yanggang Yuan, Yi Xue, Changying Xing, Bo Zhang.

Podocytes are a crucial cellular component in maintaining the glomerular filtration barrier, and their injury is the major determinant in the development of albuminuria and diabetic kidney disease (DKD). Podocytes are rich in mitochondria and heavily dependent on them for energy to maintain normal functions. Emerging evidence suggests that mitochondrial dysfunction is a key driver in the pathogenesis of podocyte injury in DKD. Impairment of mitochondrial function results in an energy crisis, oxidative stress, inflammation, and cell death. In this review, we summarize the recent advances in the molecular mechanisms that cause mitochondrial damage and illustrate the impact of mitochondrial injury on podocytes. The related mitochondrial pathways involved in podocyte injury in DKD include mitochondrial dynamics and mitophagy, mitochondrial biogenesis, mitochondrial oxidative phosphorylation and oxidative stress, and mitochondrial protein quality control. Furthermore, we discuss the role of mitochondria-associated membranes (MAMs) formation, which is intimately linked with mitochondrial function in podocytes. Finally, we examine the experimental evidence exploring the targeting of podocyte mitochondrial function for treating DKD and conclude with a discussion of potential directions for future research in the field of mitochondrial dysfunction in podocytes in DKD.

Keywords: diabetic kidney disease; injury; mitochondrial dysfunction; podocytes; therapeutic strategies

DOI: https://doi.org/10.3389/fcell.2022.832887