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1. Peroxisomal Stress Response and Inter-Organelle Communication in Cellular Homeostasis and Aging

   https://doi.org/10.3390/antiox11020192  

   Kim, J ; Bai, H ( January 2022 , Antioxidants)

   Santos, AL (Ed.)

   Peroxisomes are key regulators of cellular and metabolic homeostasis. These organelles play important roles in redox metabolism, the oxidation of very-long-chain fatty acids (VLCFAs), and the biosynthesis of ether phospholipids. Given the essential role of peroxisomes in cellular homeostasis, peroxisomal dysfunction has been linked to various pathological conditions, tissue functional decline, and aging. In the past few decades, a variety of cellular signaling and metabolic changes have been reported to be associated with defective peroxisomes, suggesting that many cellular processes and functions depend on peroxisomes. Peroxisomes communicate with other subcellular organelles, such as the nucleus, mitochondria, endoplasmic reticulum (ER), and lysosomes. These inter-organelle communications are highly linked to the key mechanisms by which cells surveil defective peroxisomes and mount adaptive responses to protect them from damages. In this review, we highlight the major cellular changes that accompany peroxisomal dysfunction and peroxisomal inter-organelle communication through membrane contact sites, metabolic signaling, and retrograde signaling. We also discuss the age-related decline of peroxisomal protein import and its role in animal aging and age-related diseases. Unlike other organelle stress response pathways, such as the unfolded protein response (UPR) in the ER and mitochondria, the cellular signaling pathways that mediate stress responses to malfunctioning peroxisomes have not been systematically studied and investigated. Here, we coin these signaling pathways as “peroxisomal stress response pathways”. Understanding peroxisomal stress response pathways and how peroxisomes communicate with other organelles are important and emerging areas of peroxisome research. 

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2. Distinct mechanisms regulating mechanical force-induced Ca2+ signals at the plasma membrane and the ER in human MSCs

   https://doi.org/10.7554/eLife.04876  

   Kim, Tae-Jin ; Joo, Chirlmin ; Seong, Jihye ; Vafabakhsh, Reza ; Botvinick, Elliot L ; Berns, Michael W ; Palmer, Amy E ; Wang, Ning ; Ha, Taekjip ; Jakobsson, Eric ; et al ( February 2015 , eLife)

   It is unclear that how subcellular organelles respond to external mechanical stimuli. Here, we investigated the molecular mechanisms by which mechanical force regulates Ca2+ signaling at endoplasmic reticulum (ER) in human mesenchymal stem cells. Without extracellular Ca2+, ER Ca2+ release is the source of intracellular Ca2+ oscillations induced by laser-tweezer-traction at the plasma membrane, providing a model to study how mechanical stimuli can be transmitted deep inside the cell body. This ER Ca2+ release upon mechanical stimulation is mediated not only by the mechanical support of cytoskeleton and actomyosin contractility, but also by mechanosensitive Ca2+ permeable channels on the plasma membrane, specifically TRPM7. However, Ca2+ influx at the plasma membrane via mechanosensitive Ca2+ permeable channels is only mediated by the passive cytoskeletal structure but not active actomyosin contractility. Thus, active actomyosin contractility is essential for the response of ER to the external mechanical stimuli, distinct from the mechanical regulation at the plasma membrane.

    

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3. Protocols for Generating Surfaces and Measuring 3D Organelle Morphology Using Amira

   https://doi.org/doi.org/10.3390/cells11010065  

   Garza-Lopez, E. ; Vue, Z. ; Katti, P. ; Neikirk, K. ; Biete, M. ; Lam, J. ; Beasley, H.K. ; Marshall, A.G. ; Rodman, T. ; Christensen, T. ; et al ( January 2022 , Cells)

   High-resolution 3D images of organelles are of paramount importance in cellular biology. Although light microscopy and transmission electron microscopy (TEM) have provided the standard for imaging cellular structures, they cannot provide 3D images. However, recent technological advances such as serial block-face scanning electron microscopy (SBF-SEM) and focused ion beam scanning electron microscopy (FIB-SEM) provide the tools to create 3D images for the ultrastructural analysis of organelles. Here, we describe a standardized protocol using the visualization software, Amira, to quantify organelle morphologies in 3D, thereby providing accurate and reproducible measurements of these cellular substructures. We demonstrate applications of SBF-SEM and Amira to quantify mitochondria and endoplasmic reticulum (ER) structures. 

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4. Identification of a Golgi-localized peptide reveals a minimal Golgi-targeting motif

   https://doi.org/10.1091/mbc.E22-03-0091  

   Navarro, Alexandra P. ; Cheeseman, Iain M. ( October 2022 , Molecular Biology of the Cell)

   Munson, Mary (Ed.)

   Prior work has identified signal sequences and motifs that are necessary and sufficient to target proteins to specific subcellular regions and organelles such as the plasma membrane, nucleus, endoplasmic reticulum, and mitochondria. In contrast, minimal sequence motifs that are sufficient for Golgi localization remain largely elusive. In this work, we identified a 37–amino acid alternative open reading frame (altORF) within the mRNA of the centromere protein CENP-R. This altORF peptide localizes specifically to the cytoplasmic surface of the Golgi apparatus. Through mutational analysis, we identify a minimal 10–amino acid sequence and a critical cysteine residue that are necessary and sufficient for Golgi localization. Pharmacological perturbations suggest that this peptide undergoes lipid modification to promote its localization. Together, our work defines a minimal sequence that is sufficient for Golgi targeting and provide a valuable Golgi marker for live cell imaging. 

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5. ATF4‐dependent increase in mitochondrial‐endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle

   https://doi.org/10.1002/jcp.31204  

   Hinton, Jr., Antentor ; Katti, Prasanna ; Mungai, Margaret ; Hall, Duane D. ; Koval, Olha ; Shao, Jianqiang ; Vue, Zer ; Lopez, Edgar Garza ; Rostami, Rahmati ; Neikirk, Kit ; et al ( February 2024 , Journal of Cellular Physiology)

   Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein‐ and lipid‐enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca²⁺, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle‐specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin‐2, a known MERC protein. In the present study, we tested the hypothesis thatOpa1downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice andDrosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. ReducingAtf4expression prevented the OPA1‐loss‐induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4‐dependent manner.

    

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