bims-mecosi 2023-04-16 papers

Issue of 2023‒04‒16
seven papers selected by
Verena Kohler

Dev Cell. 2023 Apr 10. pii: S1534-5807(23)00098-9. [Epub ahead of print]58(7): 597-615.e10

Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome.

Ji Geng, Tejinder Pal Khaket, Jie Pan, Wen Li, Yan Zhang, Yong Ping, Maria Inmaculada Cobos Sillero, Bingwei Lu.

Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), the most prevalent form of inherited intellectual disability. Here, we show that FMRP interacts with the voltage-dependent anion channel (VDAC) to regulate the formation and function of endoplasmic reticulum (ER)-mitochondria contact sites (ERMCSs), structures that are critical for mitochondrial calcium (mito-Ca2+) homeostasis. FMRP-deficient cells feature excessive ERMCS formation and ER-to-mitochondria Ca2+ transfer. Genetic and pharmacological inhibition of VDAC or other ERMCS components restored synaptic structure, function, and plasticity and rescued locomotion and cognitive deficits of the Drosophila dFmr1 mutant. Expressing FMRP C-terminal domain (FMRP-C), which confers FMRP-VDAC interaction, rescued the ERMCS formation and mito-Ca2+ homeostasis defects in FXS patient iPSC-derived neurons and locomotion and cognitive deficits in Fmr1 knockout mice. These results identify altered ERMCS formation and mito-Ca2+ homeostasis as contributors to FXS and offer potential therapeutic targets.

Keywords: ER-mitochondria contact site; ERMCS; FMRP; FXS; VDAC; fragile X messenger ribonucleoprotein; fragile X syndrome; mito-Ca(2+) homeostasis; mitochondrial calcium homeostasis; voltage-dependent anion channel

DOI: https://doi.org/10.1016/j.devcel.2023.03.002

Antioxid Redox Signal. 2023 Apr 13.

Mitofusin2 ameliorated ER stress and mitochondrial ROS through maintaining mitochondria-associated ER membrane integrity in cisplatin-induced acute kidney injury.

Yu-Ting Liu, Hao Zhang, Shao-Bin Duan, Jianwen Wang, Hong Chen, Ming Zhan, Wei Zhang, Ai-Mei Li, Yan Liu, Yang Yang, Shikun Yang.

AIMS: This study investigated the regulatory effect of Mitofusin2 (Mfn2) on mitochondria-associated endoplasmic reticulum membrane (MAMs) integrity and cellular injury in cisplatin-induced acute kidney injury (CP-AKI).RESULTS: CP- AKI mice exhibited decreased expression of Mfn2, increased expression of phosphorylated adenosine monophosphate activated protein kinase (P-AMPK), abnormal mitochondrial morphology, and reduced MAMs integrity, accompanied by the activation of mitochondrial ROS and ER stress (IRE1 and PERK pathways). In in vitro studies, CP-induced mitochondrial ROS, ER stress activation, and increased apoptosis were accompanied by the downregulation of Mfn2 and MAMs integrity reduction in Boston University mouse proximal tubular (BUMPT) cells and human proximal tubular epithelial (HK-2) cells. Pretreatment of BUMPT cells with the Mfn2 plasmid partially restored the integrity of MAMs, negatively controled IRE1 and PERK pathways, and inhibited cell apoptosis. In contrast, ER stress and MAMs integrity violations were increased after Mfn2 siRNA treatment in HK-2 cells under CP treatment. Co-immunoprecipitation analysis demonstrated that Mfn2 interacted with PERK and IRE1. Furthermore, the AMPK agonist, AICAR had a similar effect like Mfn2 plasmid in the regulation of ER stress and MAMs. Conversely, the ER stress inhibitor, 4-PBA, had no effect on the expression of Mfn2 and MAMs integrity.
INNOVATION AND CONCLUSION: This is the first study to explore the association between MAMs, ER stress, and Mfn2 in CP-AKI. Downregulation of Mfn2 expression abolished the MAMs integrity and induced ER stress, mitochondrial ROS, and tubular cell apoptosis. This suggests that the Mfn2-MAMs pathway is a potential therapeutic target in CP-AKI.

DOI: https://doi.org/10.1089/ars.2022.0178

Biochim Biophys Acta Mol Basis Dis. 2023 Apr 10. pii: S0925-4439(23)00082-0. [Epub ahead of print] 166716

Hakuna MAM-Tata: Investigating the role of mitochondrial-associated membranes in ALS.

Anna Fernàndez Bernal, Natàlia Mota, Reinald Pamplona, Estela Area-Gomez, Manuel Portero-Otin.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant heterogeneity in pathogenic and clinical terms, MN demise ultimately unifies patients. Across the many disturbances in neuronal biology present in the disease and its models, two common trends are loss of calcium homeostasis and dysregulations in lipid metabolism. Since both mitochondria and endoplasmic reticulum (ER) are essential in these functions, their intertwin through the so-called mitochondrial-associated membranes (MAMs) should be relevant in this disease. In this review, we present a short overview of MAMs functional aspects and how its dysfunction could explain a substantial part of the cellular disarrangements in ALS's natural history. MAMs are hubs for lipid synthesis, integrating glycerophospholipids, sphingolipids, and cholesteryl ester metabolism. These lipids are essential for membrane biology, so there should be a close coupling to cellular energy demands, a role that MAMs may partially fulfill. Not surprisingly, MAMs are also host part of calcium signaling to mitochondria, so their impairment could lead to mitochondrial dysfunction, affecting oxidative phosphorylation and enhancing the vulnerability of MNs. We present data supporting that MAMs' maladaptation could be essential to MNs' vulnerability in ALS.

Keywords: Calcium metabolism; Lipid synthesis; Mitochondria; Neurodegeneration; TDP-43

DOI: https://doi.org/10.1016/j.bbadis.2023.166716

Circ Res. 2023 Apr 14.

Enhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle Remodeling.

Zuzana Nichtová, Celia Fernandez-Sanz, Sergio De La Fuente, Yuexing Yuan, Stephen Hurst, Sebastian Lanvermann, Hui-Ying Tsai, David Weaver, Ariele Baggett, Christopher Thompson, Cedric Bouchet-Marquis, Péter Várnai, Erin L Seifert, Gerald W Dorn, Shey-Shing Sheu, György Csordás.

BACKGROUND: Cardiac contractile function requires high energy from mitochondria, and Ca2+ from the sarcoplasmic reticulum (SR). Via local Ca2+ transfer at close mitochondria-SR contacts, cardiac excitation feedforward regulates mitochondrial ATP production to match surges in demand (excitation-bioenergetics coupling). However, pathological stresses may cause mitochondrial Ca2+ overload, excessive reactive oxygen species production and permeability transition, risking homeostatic collapse and myocyte loss. Excitation-bioenergetics coupling involves mitochondria-SR tethers but the role of tethering in cardiac physiology/pathology is debated. Endogenous tether proteins are multifunctional; therefore, nonselective targets to scrutinize interorganelle linkage. Here, we assessed the physiological/pathological relevance of selective chronic enhancement of cardiac mitochondria-SR tethering.METHODS: We introduced to mice a cardiac muscle-specific engineered tether (linker) transgene with a fluorescent protein core and deployed 2D/3D electron microscopy, biochemical approaches, fluorescence imaging, in vivo and ex vivo cardiac performance monitoring and stress challenges to characterize the linker phenotype.
RESULTS: Expressed in the mature cardiomyocytes, the linker expanded and tightened individual mitochondria-junctional SR contacts; but also evoked a marked remodeling with large dense mitochondrial clusters that excluded dyads. Yet, excitation-bioenergetics coupling remained well-preserved, likely due to more longitudinal mitochondria-dyad contacts and nanotunnelling between mitochondria exposed to junctional SR and those sealed away from junctional SR. Remarkably, the linker decreased female vulnerability to acute massive β-adrenergic stress. It also reduced myocyte death and mitochondrial calcium-overload-associated myocardial impairment in ex vivo ischemia/reperfusion injury.
CONCLUSIONS: We propose that mitochondria-SR/endoplasmic reticulum contacts operate at a structural optimum. Although acute changes in tethering may cause dysfunction, upon chronic enhancement of contacts from early life, adaptive remodeling of the organelles shifts the system to a new, stable structural optimum. This remodeling balances the individually enhanced mitochondrion-junctional SR crosstalk and excitation-bioenergetics coupling, by increasing the connected mitochondrial pool and, presumably, Ca2+/reactive oxygen species capacity, which then improves the resilience to stresses associated with dysregulated hyperactive Ca2+ signaling.

Keywords: ischemia; myocyte; reperfusion; sarcoplasmic reticulum; transgene

DOI: https://doi.org/10.1161/CIRCRESAHA.122.321833

J Cell Sci. 2023 Apr 11. pii: jcs.260976. [Epub ahead of print]

Molecular basis of Climp63-mediated ER lumen spacing.

Lu Xu, Yun Xiang, Junjie Hu.

The width of cisternal structures in the endoplasmic reticulum (ER) is maintained by ER-resident protein Climp63. Self-association of the Climp63 luminal domain (LD), even though moderate, plays a key role in shaping ER sheets. However, the molecular basis of luminal spacing remains elusive. Here, we analyze the homotypic interactions of the Climp63 LD using AI-predicted structures. The LD is highly alpha-helical, with a flexible leading helix followed by a five-helix bundle (5HB). Charge-based trans associations are formed between the tip of the 5HB and the C-terminus of the LD, consistent with generating a width of ∼50 nm for ER sheets. The leading helix of the LD is dispensable for homotypic interactions, but packing of the 5HB regulates self-association. The density of Climp63, likely reflecting the strength of cis interactions, influences the ER width, which is maintained by trans interactions. These results indicate that a general principle in maintaining membrane tethering is multi-modular self-association.

Keywords: Endoplasmic reticulum; Membrane tethering; Structural prediction

DOI: https://doi.org/10.1242/jcs.260976

Int J Mol Sci. 2023 Apr 01. pii: 6593. [Epub ahead of print]24(7):

PI4P-Containing Vesicles from Golgi Contribute to Mitochondrial Division by Coordinating with Polymerized Actin.

Xinxin Duan, Yunfei Wei, Meng Zhang, Wenting Zhang, Yue Huang, Yu-Hui Zhang.

Golgi-derived PI4P-containing vesicles play important roles in mitochondrial division, which is essential for maintaining cellular homeostasis. However, the mechanism of the PI4P-containing vesicle effect on mitochondrial division is unclear. Here, we found that actin appeared to polymerize at the contact site between PI4P-containing vesicles and mitochondria, causing mitochondrial division. Increasing the content of PI4P derived from the Golgi apparatus increased actin polymerization and reduced the length of the mitochondria, suggesting that actin polymerization through PI4P-containing vesicles is involved in PI4P vesicle-related mitochondrial division. Collectively, our results support a model in which PI4P-containing vesicles derived from the Golgi apparatus cooperate with actin filaments to participate in mitochondrial division by contributing to actin polymerization, which regulates mitochondrial dynamics. This study enriches the understanding of the pathways that regulate mitochondrial division and provides new insight into mitochondrial dynamics.

Keywords: PI4P-containing vesicle; actin polymerization; interaction; mitochondrial division; super-resolution imaging

DOI: https://doi.org/10.3390/ijms24076593