Organelle <p><span style="font-weight: 400;">The specialized structures within a cell that we know as organelles have crucial and still fascinatingly mysterious influence in the larger story of an organism. Today our understanding of organelles and their dynamics, including morphological changes, biogenesis, trafficking, or interplaying among different organelles is evolving. Research investigating these dynamics and molecular mechanisms, especially in the context of the pathophysiology of human diseases, is essential and has only just begun. What we understand about organelles and their role in human diseases can be expected to expand greatly and </span><em><span style="font-weight: 400;">Organelle</span></em><span style="font-weight: 400;"> is dedicated to making that happen. </span></p> Organelle Interface Publishing en-US Organelle 2834-7714 Regulation of mitochondrial function by FOXOs in ischemic stroke and Alzheimer’s disease <p><strong>Transcriptional control is a pivotal mechanism governing various cellular processes. FOXO proteins, a subgroup of the forkhead family of transcription factors, play a key role in determining cell fate. The localization and function of FOXO proteins are regulated by post-translational modifications to control target gene expression, with a pronounced impact on various aspects of mitochondrial function, including mitochondrial dynamics, biogenesis, and quality control. Mitochondria stand out as the primary target of FOXO transcription factors, which recruit downstream signaling factors to govern mitochondrial processes. Essential signaling pathways are modulated by FOXOs, exemplified by their </strong><strong>regulation of mitochondrial biogenesis through SIRT1-Pgc1a and NRF1-TFAM, as well as their influence on mitochondrial dynamics involving Mfn1, Mfn2, Drp1, and Fis1. Furthermore, FOXOs demonstrate the ability to upregulate and downregulate genes that serve as modulators in oxidative and apoptosis cascades. The functional role of FOXO proteins is highly context-dependent, varying with cell type, organ, and specific FOXO isoform. Notably, FOXOs emerge as prominent players in various pathological conditions, including ischemic conditions, neurodegenerative diseases, cancer, and metabolic disorders. Unraveling the complex role of FOXOs in mammalian cell pathology positions them </strong><strong>as promising therapeutic targets receptive to pharmacological treatment. This review aims to provide insights into the intricate roles of FOXOs in mitochondria, illuminating their potential as therapeutic targets amenable to pharmacological intervention in diverse pathological contexts, particularly in ischemic stroke and Alzheimer’s disease.</strong></p> Yasin Asadi Hongmin Wang Copyright (c) 2024 Organelle 2024-05-15 2024-05-15 1 1 10.61747/0ifp.202403001 Intricate roles of spacers and stickers of Arg-rich C9ORF72 dipeptide repeat proteins; from toxicity to targeting to membraneless organelles <p><strong><em>C9ORF72</em>, one of the most common genes implicated in amyotrophic lateral sclerosis and frontotemporal dementia, induces neurodegeneration through various pathways. The most notable is interference through liquid-liquid phase separation (LLPS). LLPS is a biophysical phenomenon involved in many fundamental biological processes, such as the formation of membraneless organelles (MLOs), transcription, and nucleocytoplasmic transport. The Arg-rich dipeptide repeat proteins (R-DPRs) produced from the aberrant <em>C9ORF72</em> gene are highly charged and are incorporated into the phase-separated MLOs, inhibiting their functions. However, the detailed molecular mechanism remains to be elucidated. Recently, we analyzed the structure-function relationship of R-DPRs and clarified the mechanism by which the sticker Arg and the spacer Pro/Gly regulate cytotoxicity and subcellular localization. Natural R-DPRs contribute to the localization of specific MLOs. In this review, we discuss the roles of the sticker and spacer of R-DPRs in the LLPS and how they regulate subcellular localization, protein-protein interaction, and neurotoxicity.</strong></p> Tamami Miyagi Kohsuke Kanekura Copyright (c) 2023 Organelle 2023-12-13 2023-12-13 1 1 10.61747/0ifp.202311001