bims-mecosi 2022-08-07 papers

Issue of 2022‒08‒07
five papers selected by
Verena Kohler

Biol Cell. 2022 Aug 04.

CMT2A-linked mitochondrial hyperfusion-driving mutant MFN2 perturbs ER-mitochondrial associations and Ca2+ homeostasis.

Rajdeep Das, Subhrangshu Das, Saikat Chakrabarti, Oishee Chakrabarti.

Mitofusin2 (MFN2), an important molecular player that regulates mitochondrial fusion, also helps maintain the inter-organellar contact sites, referred as mitochondria associated membranes (MAMs) that exist between the ER and mitochondria. Here we show that a mutant of MFN2, R364W-MFN2, linked with the Charcot Marie Tooth disease, promotes mitochondrial hyperfusion, alters ER mitochondrial associations at the MAM junctions and perturbs inter-organellar calcium homeostasis. Such hyperfused mitochondria are also predisposed towards stress and undergo rapid fission upon induction of mild stress. Thus, here we report that presence of the R364W-MFN2 mutation makes cells susceptible towards stress, thus negatively affecting cellular health. This article is protected by copyright. All rights reserved.

Keywords: CMT2A-linked MFN2 mutant; DRP1; ER-mitochondrial associations; mitochondrial hyperfusion

DOI: https://doi.org/10.1111/boc.202100098

Curr Biol. 2022 Jul 31. pii: S0960-9822(22)01115-0. [Epub ahead of print]

A polarized supercell produces specialized metabolites in cannabis trichomes.

Samuel J Livingston, Kim H Rensing, Jonathan E Page, A Lacey Samuels.

For centuries, humans have cultivated cannabis for the pharmacological properties that result from consuming its specialized metabolites, primarily cannabinoids and terpenoids. Today, cannabis is a multi-billion-dollar industry whose existence rests on the biological activity of tiny cell clusters, called glandular trichomes, found mainly on flowers. Cannabinoids are toxic to cannabis cells,1 and how the trichome cells can produce and secrete massive quantities of lipophilic metabolites is not known.1 To address this gap in knowledge, we investigated cannabis glandular trichomes using ultra-rapid cryofixation, quantitative electron microscopy, and immuno-gold labeling of cannabinoid pathway enzymes. We demonstrate that the metabolically active cells in cannabis form a "supercell," with extensive cytoplasmic bridges across the cell walls and a polar distribution of organelles adjacent to the apical surface where metabolites are secreted. The predicted metabolic role of the non-photosynthetic plastids is supported by unusual membrane arrays in the plastids and the localization of the start of the cannabinoid/terpene pathway in the stroma of the plastids. Abundant membrane contact sites connected plastid paracrystalline cores with the plastid envelope, plastid with endoplasmic reticulum (ER), and ER with plasma membrane. The final step of cannabinoid biosynthesis, catalyzed by tetrahydrocannabinolic acid synthase (THCAS), was localized in the cell-surface wall facing the extracellular storage cavity. We propose a new model of how the cannabis cells can support abundant metabolite production, with emphasis on the key role of membrane contact sites and extracellular THCA biosynthesis. This new model can inform synthetic biology approaches for cannabinoid production in yeast or cell cultures.

Keywords: TEM; THCAS; cannabinoids; cannabis; glandular trichome; immunolocalization; membrane contact site; plastid; polarization; syncytium

DOI: https://doi.org/10.1016/j.cub.2022.07.014

J Cell Biol. 2022 Sep 05. pii: e202106190. [Epub ahead of print]221(9):

DeepContact: High-throughput quantification of membrane contact sites based on electron microscopy imaging.

Liqing Liu, Shuxin Yang, Yang Liu, Xixia Li, Junjie Hu, Li Xiao, Tao Xu.

Membrane contact site (MCS)-mediated organelle interactions play essential roles in the cell. Quantitative analysis of MCSs reveals vital clues for cellular responses under various physiological and pathological conditions. However, an efficient tool is lacking. Here, we developed DeepContact, a deep-learning protocol for optimizing organelle segmentation and contact analysis based on label-free EM. DeepContact presents high efficiency and flexibility in interactive visualizations, accommodating new morphologies of organelles and recognizing contacts in versatile width ranges, which enables statistical analysis of various types of MCSs in multiple systems. DeepContact profiled previously unidentified coordinative rearrangements of MCS types in cultured cells with combined nutritional conditions. DeepContact also unveiled a subtle wave of ER-mitochondrial entanglement in Sertoli cells during the seminiferous epithelial cycle, indicating its potential in bridging MCS dynamics to physiological and pathological processes.

DOI: https://doi.org/10.1083/jcb.202106190

Neurobiol Dis. 2022 Jul 27. pii: S0969-9961(22)00224-8. [Epub ahead of print] 105832

Altered SYNJ2BP-mediated mitochondrial-ER contacts in motor neuron disease.

Naemeh Pourshafie, Ester Masati, Amber Lopez, Eric Bunker, Allison Snyder, Nancy A Edwards, Audrey M Winkelsas, Kenneth H Fischbeck, Christopher Grunseich.

Synaptojanin 2 binding protein (SYNJ2BP) is an outer mitochondrial membrane protein with a cytosolic PDZ domain that functions as a cellular signaling hub. Few studies have evaluated its role in disease. Here we use induced pluripotent stem cell (iPSC)-derived motor neurons and post-mortem tissue from patients with two hereditary motor neuron diseases, spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis type 4 (ALS4), and show that SYNJ2BP expression is increased in diseased motor neurons. Similarly, we show that SYNJ2BP expression increases in iPSC-derived motor neurons undergoing stress. Using proteomic analysis, we found that elevated SYNJ2BP alters the cellular distribution of mitochondria and increases mitochondrial-ER membrane contact sites. Furthermore, decreasing SYNJ2BP levels improves mitochondrial oxidative function in the diseased motor neurons. Together, our observations offer new insight into the molecular pathology of motor neuron disease and the role of SYNJ2BP in mitochondrial dysfunction.

Keywords: Motor neuron disease; Polyglutamine disease; Spinal and bulbar muscular atrophy

DOI: https://doi.org/10.1016/j.nbd.2022.105832

Food Funct. 2022 Aug 04.

Zeaxanthin remodels cytoplasmic lipid droplets via β3-adrenergic receptor signaling and enhances perilipin 5-mediated lipid droplet-mitochondrion interactions in adipocytes.

Jiahan Xie, Huimin Liu, Wandi Yin, Sitong Ge, Zhibo Jin, Mingzhu Zheng, Dan Cai, Meihong Liu, Jingsheng Liu.

Cytoplasmic lipid droplets (LDs), which are remarkably dynamic, neutral lipid storage organelles, play fundamental roles in lipid metabolism and energy homeostasis. Both the dynamic remodeling of LDs and LD-mitochondrion interactions in adipocytes are effective mechanisms to ameliorate obesity and related comorbidities. Zeaxanthin (ZEA) is a natural carotenoid and has beneficial effects on anti-obesity. However, the underlying mechanisms of ZEA on LD modulation are still unclear. In the present study, ZEA efficiently inhibited LD accumulation and attenuated adipocyte proliferation by arresting the cell cycle. ZEA drove transcriptional alterations to reprogram a lipid oxidative metabolism phenotype in mature 3T3-L1 adipocytes. ZEA significantly decreased the TAG and FA content and modulated the dynamic alterations of LDs by upregulating the expression of lipases and the LD-mitochondrion contact site protein, perilipin 5 (PLIN5), and downregulating the LD fusion protein, fat-specific protein 27 (FSP27). Mechanistically, ZEA stimulated LD remodeling and ameliorated mitochondrial defects caused by large and unilocular LD accumulation by activating β3-adrenergic receptor (β3-AR) signaling. Furthermore, the knockdown of PLIN5 impaired the LD-mitochondrion interactions, thereby disrupting the role of ZEA in promoting mitochondrial fatty acid oxidation and respiratory chain operation. Collectively, the present study demonstrates that ZEA induces LD structural and metabolic remodeling by activating β3-AR signaling and enhances PLIN5-mediated LD-mitochondrion interactions in hypertrophic white adipocytes, thereby enhancing oxidative capacity, and has the potential as a nutritional intervention for the prevention and treatment of obesity and associated metabolic syndrome.

DOI: https://doi.org/10.1039/d2fo01094a