Editorial Material
Cell Biology
Yalan Wang, Hongyan Wang, Chenji Wang
Summary: In neuronal ceroid lipofuscinoses (NCLs), mutations in the KCTD7 gene lead to lysosomal dysfunction and macroautophagic/autophagic defects, resulting in the accumulation of lysosomal storage deposits. Our study demonstrates that KCTD7 is a key player in maintaining lysosomal and autophagic homeostasis, and it is biochemically linked with CLN5, another NCL causative gene, in a common neurodegenerative pathway.
Review
Cell Biology
Srimanta Patra, Shankargouda Patil, Daniel J. J. Klionsky, Sujit K. K. Bhutia
Summary: Recent studies have shown that lysosomes, traditionally thought of as static garbage disposals, play a dynamic and multi-functional role in maintaining cellular homeostasis. Lysosomes sense cellular metabolic status and regulate the balance between catabolism and anabolism through signaling pathways, proteins, and transcription factors. Lysosomes also interact with other organelles and their positioning and motility are critical for cellular adaptation. Furthermore, lysosomes can orchestrate different cell death mechanisms to maintain cellular homeostasis, highlighting their central role as a signaling hub.
JOURNAL OF CELLULAR PHYSIOLOGY
(2023)
Article
Cell Biology
Manuela Santo, Ivan Conte
Summary: This article reviews the recent research progress on the role of lysosomes in retinal degenerative diseases and the development of effective lysosomal-based therapies.
Review
Biochemistry & Molecular Biology
Jiahao Xu, Jing Gu, Wenjun Pei, Yao Zhang, Lizhuo Wang, Jialin Gao
Summary: As a self-degrading and highly conserved survival mechanism, autophagy plays a crucial role in cell survival and recycling. The discovery of autophagy-related genes has revolutionized our understanding of autophagy. Lysosomal membrane proteins (LMPs) are vital in regulating autophagy and their dysfunction is associated with neurodegenerative diseases and cancer. This review focuses on the roles of LMPs in different stages of autophagy and their link to related diseases.
Review
Medicine, Research & Experimental
Giancarlo Parenti, Diego L. Medina, Andrea Ballabio
Summary: Lysosomal storage diseases are metabolic disorders caused by deficiencies in lysosomal function components. Understanding of lysosomal biology has evolved from organelles involved in catabolic pathways to dynamic elements involved in multiple cellular functions and capable of adapting to environmental stimuli. Novel technologies based on high-throughput approaches have greatly contributed to the characterization of lysosomal biology and dysfunction.
EMBO MOLECULAR MEDICINE
(2021)
Editorial Material
Cell Biology
Antonio Monaco, Alessandro Fraldi
Summary: Mucopolysaccharidoses (MPS) are inherited metabolic diseases with strong neurological involvement. Impairment of autophagy pathway is a key factor driving neurodegeneration in MPS, particularly downstream of the GAG storage.
Review
Biochemistry & Molecular Biology
Gianluca Scerra, Valeria De Pasquale, Melania Scarcella, Maria Gabriella Caporaso, Luigi Michele Pavone, Massimo D'Agostino
Summary: Lysosomal storage diseases are inherited disorders characterized by the accumulation of undegraded substances, leading to lysosomal dysfunction and damage to multiple organ systems. Recent studies have shown that the accumulation of lysosomal substrates is just the beginning of a cascade of processes that contribute to the progression of these diseases.
Review
Neurosciences
Luojia Wu, Yue Lin, Jiali Song, Longshan Li, Xiuqin Rao, Wei Wan, Gen Wei, Fuzhou Hua, Jun Ying
Summary: This review summarizes the structural, modulatory, and functional properties of TMEM175, an ion channel in lysosomal membrane involved in maintaining lysosomal acidity. The relevance of TMEM175 to neurological disorders is discussed, and its potential as a therapeutic target for neurodegenerative diseases is explored.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Cell Biology
Tsutomu Tanaka, Blake M. Warner, Drew G. Michael, Hiroyuki Nakamura, Toshio Odani, Hongen Yin, Tatsuya Atsumi, Masayuki Noguchi, John A. Chiorini
Summary: In patients with SS (Sjogren's syndrome), increased expression of LAMP3 has been associated with increased apoptosis and accumulation of autoantigens. Studies showed that LAMP3 expression led to lysosomal membrane permeabilization, affecting autophagic flux and caspase activation. This highlights the significant role of LAMP3 expression in the pathogenesis of SS.
Review
Cell Biology
Andre R. A. Marques, Cristiano Ramos, Gisela Machado-Oliveira, Otilia V. Vieira
Summary: Atherosclerosis is a progressive chronic disease with lysosomal dysfunction playing a central role in its development. Dysfunction of lysosomes leads to inefficient degradation of lipoproteins, impacting cellular homeostasis and disease progression. This phenomenon extends beyond inherited lysosomal storage disorders, influencing the progression of various acquired human pathologies like neurodegenerative diseases and cardiovascular diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Cell Biology
Myeong Uk Kuk, Yun Haeng Lee, Jae Won Kim, Su Young Hwang, Joon Tae Park, Sang Chul Park
Summary: Lysosomal storage disease (LSD) is a genetic metabolic disorder with no effective treatment to restore normal levels. The crosstalk between lysosomes and mitochondria is crucial for cellular homeostasis, and the deficiency of lysosome enzymes in LSD leads to deterioration of the mitochondrial respiratory chain.
Editorial Material
Cell Biology
Alessandro Luciani, Olivier Devuyst
Summary: This study identified the role of CTNS deficiency in triggering dedifferentiation and dysfunction of PT cells, leading to kidney disease and metabolic complications. It was found that CTNS deficiency stimulates activation of the MTORC1 pathway, diverting cell trajectories towards growth and proliferation, disrupting homeostasis and specialized functions. Treatment with low doses of rapamycin can correct lysosome function and differentiation, ameliorating PT dysfunction in preclinical models of cystinosis.
Review
Biochemistry & Molecular Biology
Rebecca Maechtel, Fanni Annamaria Boros, Jan Philipp Dobert, Philipp Arnold, Friederike Zunke
Summary: Lysosomes are acidic organelles responsible for recycling cellular components and can cause lysosomal dysfunction and LSDs when there is reduced enzymatic activity. Neurons are particularly susceptible to lysosomal dysfunction, leading to neurological symptoms. There are genetic associations between LSDs and Parkinson's disease, indicating common cellular mechanisms.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Delong Meng, Qianmei Yang, Chase H. Melick, Brenden C. Park, Ting-Sung Hsieh, Adna Curukovic, Mi-Hyeon Jeong, Junmei Zhang, Nicholas G. James, Jenna L. Jewell
Summary: The study identified ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1) as a critical regulator of mTORC1, which inhibits cell growth through preventing the lysosomal transport and activation of mTORC1, and is also an independent prognostic factor for the overall survival of pancreatic cancer patients.
Review
Biochemistry & Molecular Biology
Yukiko Sasazawa, Nobutaka Hattori, Shinji Saiki
Summary: Lysosomal positioning is crucial for cellular homeostasis, and recent research has focused on the mechanisms of lysosomal trafficking, including the role of adapter protein JIP4. This article outlines the latest findings on lysosomal trafficking and JIP4 functions, as well as discussing the association of JIP family proteins with neuronal diseases. Chemical manipulation of lysosomal positioning shows promise as a therapeutic approach for these neurological conditions.
Editorial Material
Cell Biology
Susmita Kaushik, Yves R. Juste, Ana Maria Cuervo
Summary: The circadian clock and chaperone-mediated autophagy (CMA) have an interdependent relationship. CMA selectively degrades core clock proteins, modulating circadian rhythm. Loss of CMA disrupts physiological circadian cycling, similar to defects observed in aging. The circadian clock temporally regulates CMA activity in different tissues, contributing to remodeling of a distinct subproteome at different times.
Editorial Material
Cell Biology
Jorge Moscat, Ana Maria Cuervo, Maria T. Diaz-Meco
Summary: The mechanisms of immunosurveillance and immunoevasion are crucial in determining whether a tumor cell survives and the role of autophagy in promoting catabolism and detoxification for transformed cells is significant in the cancer microenvironment.
Article
Biochemistry & Molecular Biology
Guillaume Corre, Ababacar Seye, Sophie Frin, Maxime Ferrand, Kathrin Winkler, Cyril Luc, Fabien Dorange, Celine J. Rocca, Anne Galy
Summary: With the increasing number of gene therapy clinical trials and drugs, it is important to standardize the methods used to evaluate the safety and effectiveness of gene therapy. This study reports the creation of stable lentiviral standards, which are cloned human cells with a known number of lentiviral vector copies in their genome. These standards can be used as reference materials for calibrating and qualifying analytical methods used to measure vector copy numbers and lentiviral vector integration sites. The study shows that digital droplet PCR (ddPCR) is more precise than quantitative PCR (qPCR) for determining vector copy numbers, and a new sensitive and specific ddPCR method was developed. Lentiviral standards should be used in all assays that assess the efficacy and safety of lentiviral gene therapy.
Article
Biotechnology & Applied Microbiology
Antonella Capuozzo, Sandro Montefusco, Vincenzo Cacace, Martina Sofia, Alessandra Esposito, Gennaro Napolitano, Eduardo Nusco, Elena Polishchuk, Maria Teresa Pizzo, Maria De Risi, Elvira De Leonibus, Nicolina Cristina Sorrentino, Diego Luis Medina
Summary: Through screening clinically approved drugs in MPS-IIIA cells, we found that fluoxetine can enhance lysosomal and autophagic functions, and improve MPS-IIIA pathology and cognitive deterioration by clearing heparan sulfate. We repurposed fluoxetine for potential MPS-IIIA therapeutics.
Review
Cell Biology
Duarte C. Barral, Leopoldo Staiano, Claudia Guimas Almeida, Dan F. Cutler, Emily R. Eden, Clare E. Futter, Antony Galione, Andre R. A. Marques, Diego Luis Medina, Gennaro Napolitano, Carmine Settembre, Otilia V. Vieira, Johannes M. F. G. Aerts, Peace Atakpa-Adaji, Gemma Bruno, Antonella Capuozzo, Elvira De Leonibus, Chiara Di Malta, Cristina Escrevente, Alessandra Esposito, Paolo Grumati, Michael J. Hall, Rita O. Teodoro, Susana S. Lopes, J. Paul Luzio, Jlenia Monfregola, Sandro Montefusco, Frances M. Platt, Roman Polishchuck, Maria De Risi, Irene Sambri, Chiara Soldati, Miguel C. Seabra
Summary: This review presents current methods used to analyze lysosome morphology, positioning, motility, and function, discussing the strategies for identifying and assessing lysosome characteristics and functions. It aims to stimulate further research on lysosomes and encourage groundbreaking discoveries on this intriguing organelle that continues to surprise and excite cell biologists.
Review
Cell Biology
Gennaro Napolitano, Chiara Di Malta, Andrea Ballabio
Summary: The mTORC1 signaling pathway integrates multiple environmental cues to regulate cell growth and metabolism. Recent studies have revealed a 'non-canonical' signaling pathway of mTORC1 that controls the function of MiT-TFE transcription factors, key regulators of cell metabolism, and responds to stimuli that converge on the lysosomal surface.
TRENDS IN CELL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Raquel Gomez-Sintes, Qisheng Xin, Juan Ignacio Jimenez-Loygorri, Mericka McCabe, Antonio Diaz, Thomas P. Garner, Xiomaris M. Cotto-Rios, Yang Wu, Shuxian Dong, Cara A. Reynolds, Bindi Patel, Pedro de la Villa, Fernando Macian, Patricia Boya, Evripidis Gavathiotis, Ana Maria Cuervo
Summary: This study identifies the mechanism of action of selective molecules that activate chaperone-mediated autophagy and develops orally bioavailable drugs with good brain exposure. These drugs stabilize the interaction between retinoic acid receptor alpha and its co-repressor, leading to selective activation of chaperone-mediated autophagy. In vivo experiments show that these drugs activate this pathway and improve retinal degeneration in a mouse model of retinitis pigmentosa.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Emmanouil Zacharioudakis, Bogos Agianian, Vasantha Kumar Mv, Nikolaos Biris, Thomas P. Garner, Inna Rabinovich-Nikitin, Amanda T. Ouchida, Victoria Margulets, Lars Ulrik Nordstrom, Joel S. Riley, Igor Dolgalev, Yun Chen, Andre J. H. Wittig, Ryan Pekson, Chris Mathew, Peter Wei, Aristotelis Tsirigos, Stephen W. G. Tait, Lorrie A. Kirshenbaum, Richard N. Kitsis, Evripidis Gavathiotis
Summary: Mitofusins are proteins that regulate mitochondrial fusion, a process with significant impact on cellular processes. This study identifies small molecules that can activate or inhibit Mitofusins' activity, thereby modulating mitochondrial fusion and functionality. Inhibition of mitochondrial fusion leads to certain physiological changes such as caspase-3/7 activation and DNA damage. The findings highlight the importance of Mitofusins' conformational changes and oligomerization in enabling mitochondrial fusion. The study provides insights into the function and regulation of Mitofusins and offers potential small molecules for pharmacological targeting.
NATURE COMMUNICATIONS
(2022)
Correction
Cell Biology
Shuhei Nakamura, Saki Shigeyama, Satoshi Minami, Takayuki Shima, Shiori Akayama, Tomoki Matsuda, Alessandra Esposito, Gennaro Napolitano, Akiko Kuma, Tomoko Namba-Hamano, Jun Nakamura, Kenichi Yamamoto, Miwa Sasai, Ayaka Tokumura, Mika Miyamoto, Yukako Oe, Toshiharu Fujita, Seigo Terawaki, Atsushi Takahashi, Maho Hamasaki, Masahiro Yamamoto, Yukinori Okada, Masaaki Komatsu, Takeharu Nagai, Yoshitsugu Takabatake, Haoxing Xu, Yoshitaka Isaka, Andrea Ballabio, Tamotsu Yoshimori
NATURE CELL BIOLOGY
(2022)
Article
Biology
Gaurav S. Choudhary, Andrea Pellagatti, Bogos Agianian, Molly A. Smith, Tushar D. Bhagat, Shanisha Gordon-Mitchell, Srabani Sahu, Sanjay Pandey, Nishi Shah, Srinivas Aluri, Ritesh Aggarwal, Sarah Aminov, Leya Schwartz, Violetta Steeples, Robert N. Booher, Murali Ramachandra, Maria Samson, Milagros Carbajal, Kith Pradhan, Teresa Bowman, Manoj M. Pillai, Britta Will, Amittha Wickrema, Aditi Shastri, Robert K. Bradley, Robert E. Martell, Ulrich G. Steidl, Evripidis Gavathiotis, Jacqueline Boultwood, Daniel T. Starczynowski, Amit Verma
Summary: The SF3B1 mutation leads to the expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models. This mutation also results in the activation of TRAF6 and NF-kB, promoting the development of leukemia.
Article
Virology
Daniel Li, Carlos Thomas, Nitisha Shrivastava, Adam Gersten, Nicholas Gadsden, Nicolas Schlecht, Nicole Kawachi, Bradley A. A. Schiff, Richard V. V. Smith, Gregory Rosenblatt, Stelby Augustine, Evripidis Gavathiotis, Robert Burk, Michael B. B. Prystowsky, Chandan Guha, Vikas Mehta, Thomas J. J. Ow
Summary: By using the conditional reprogramming (CR) method, we established a robust panel of HNSCC tumor cell lines from ethnically and racially diverse patients in the Bronx. These cell lines expressed markers of squamous identity and were able to form three-dimensional spheroids and murine models.
JOURNAL OF MEDICAL VIROLOGY
(2023)
Article
Multidisciplinary Sciences
Zhicheng Cui, Gennaro Napolitano, Mariana E. G. de Araujo, Alessandra Esposito, Jlenia Monfregola, Lukas A. A. Huber, Andrea Ballabio, James H. H. Hurley
Summary: The transcription factor TFEB is phosphorylated by mTORC1, which is unique in its mechanism and dependent on the activation of FLCN6,7. The cryogenic-electron microscopy analysis reveals that two Rag-Ragulator complexes present each TFEB molecule to mTOR active site. The non-canonical Rag dimer binds the first helix of TFEB with a RagC(GDP)-dependent aspartate clamp and plays a crucial role in TFEB phosphorylation.
Article
Oncology
Brian Geohagen, Elizabeth Zeldin, Kimberly Reidy, Tao Wang, Evripidis Gavathiotis, Yonatan Fishman, Richard LoPachin, David M. Loeb, Daniel A. Weiser
Summary: Cisplatin is an effective chemotherapeutic agent but causes irreversible systemic end-organ damage. We developed acetophenone-derived compounds that directly mitigate the side effects of cisplatin based on the hard-soft acid-base theory. Investigating organ-specific and generalized toxicity, we found that pre-treatment with acetophenones preserved normal organ function and prevented toxic effects induced by cisplatin.
TRANSLATIONAL ONCOLOGY
(2023)
Review
Pharmacology & Pharmacy
Emmanouil Zacharioudakis, Evripidis Gavathiotis
Summary: The importance of mitochondrial dynamics, specifically fusion and fission, in regulating cellular functions and fitness has been well established. Aberrant fusion or fission resulting from dysregulated mitochondrial dynamics proteins is associated with various pathologies, but pharmacological targeting of these proteins is complex. Recent studies have provided insights into the regulatory mechanisms of fusion and fission proteins, leading to the discovery of pharmacological modulators with therapeutic potential. These advances present exciting opportunities for the development of prototype therapeutics for multiple diseases.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2023)
Article
Multidisciplinary Sciences
Susmita Kaushik, Yves R. Juste, Kristen Lindenau, Shuxian Dong, Adrian Macho-Gonzalez, Olaya Santiago-Fernandez, Mericka McCabe, Rajat Singh, Evripidis Gavathiotis, Ana Maria Cuervo
Summary: This study reveals the crucial role of chaperone-mediated autophagy (CMA) in adipocyte differentiation, as it regulates adipogenesis at different steps through timely degradation of key regulatory signaling proteins and transcription factors.
