Article
Multidisciplinary Sciences
Lara Gibellini, Rebecca Borella, Anna De Gaetano, Giada Zanini, Domenico Lo Tartaro, Gianluca Carnevale, Francesca Beretti, Lorena Losi, Sara De Biasi, Milena Nasi, Mattia Forcato, Andrea Cossarizza, Marcello Pinti
Summary: Coordinated communication between mitochondria and the nucleus is crucial for cellular activities. Recent research has found that the protease Lonp1, previously believed to be exclusively located in the mitochondria, is also present in the nucleus and plays a role in the stress response.
SCIENTIFIC REPORTS
(2022)
Review
Biochemistry & Molecular Biology
Giada Zanini, Valentina Selleri, Mara Malerba, Kateryna Solodka, Giorgia Sinigaglia, Milena Nasi, Anna Vittoria Mattioli, Marcello Pinti
Summary: Lonp1 is a multifunctional enzyme that plays a crucial role in regulating mitochondrial functions in heart and skeletal muscle. It is involved in heart development, cardioprotection, myoblast differentiation, and aging-related muscle functional decline. Lonp1 is also associated with a syndrome characterized by impaired development of multiple organs and tissues. These findings highlight the importance of Lonp1 in maintaining mitochondrial homeostasis.
Article
Medicine, Research & Experimental
Mi Bai, Mengqiu Wu, Mingzhu Jiang, Jia He, Xu Deng, Shuang Xu, Jiaojiao Fan, Mengqiu Miao, Ting Wang, Yuting Li, Xiaowen Yu, Lin Wang, Yue Zhang, Songming Huang, Li Yang, Zhanjun Jia, Aihua Zhang
Summary: Mitochondria are the central metabolic hub of cells and their imbalance plays a pathogenic role in chronic kidney disease (CKD). This study found that Lon protease 1 (LONP1) expression was decreased in CKD patients and mice, and its overexpression mitigated renal injury and mitochondrial dysfunction. Mechanistically, LONP1 downregulation caused mitochondrial accumulation of HMGCS2, leading to disrupted mitochondrial function and CKD progression. A novel LONP1 activator was also identified, which attenuated renal fibrosis and mitochondrial dysfunction. These findings suggest that LONP1 is a promising therapeutic target for CKD.
EMBO MOLECULAR MEDICINE
(2023)
Article
Chemistry, Medicinal
Laura J. Kingsley, Xiaohui He, Matthew McNeill, John Nelson, Victor Nikulin, Zhiwei Ma, Wenshuo Lu, Vicki W. Zhou, Mari Manuia, Andreas Kreusch, Mu-Yun Gao, Darbi Witmer, Mei-Ting Vaillancourt, Min Lu, Sarah Greenblatt, Christian Lee, Ajay Vashisht, Steven Bender, Glen Spraggon, Pierre-Yves Michellys, Yong Jia, Jacob R. Haling, Gerald Lelais
Summary: LONP1 is an AAA+ protease essential for maintaining mitochondrial homeostasis, with its inhibitors potentially promoting cancer cell proliferation. This study describes the development of selective boronic acid-based LONP1 inhibitors and the structures of human LONP1 in complex with various inhibitors, providing valuable tools for investigating LONP1 biology.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Giada Zanini, Valentina Selleri, Anna De Gaetano, Lara Gibellini, Mara Malerba, Anna Vittoria Mattioli, Milena Nasi, Nadezda Apostolova, Marcello Pinti
Summary: This study identified three isoforms of Lonp1 protein in humans, with ISO1 and ISO2 being upregulated in various cancers while ISO3 showed no significant changes between cancer and normal tissue. Overexpression of ISO1 and ISO2 enhanced fatty acid oxidation and mitochondrial respiration in cells, leading to an increase in extracellular acidification rate and glycolysis. Additionally, the overexpression of ISO1 and ISO2 promoted anchorage-independent growth and upregulated EMT-related proteins, possibly through global metabolic reprogramming of cells.
Article
Multidisciplinary Sciences
Chun-Shik Shin, Shuxia Meng, Spiros D. Garbis, Annie Moradian, Robert W. Taylor, Michael J. Sweredoski, Brett Lomenick, David C. Chan
Summary: This study reveals that the mitochondrial protease LONP1 is essential for the mtHSP70 chaperone system, regardless of its protease activity. LONP1 plays a critical role in maintaining the solubility of DNAJA3 and mtHSP70 in the mitochondria, showing intrinsic chaperone-like activity and collaborating with mtHSP70 to stabilize protein folding intermediates.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Yuzhe He, Qianhai Ding, Wenliang Chen, Changjian Lin, Lujie Ge, Chenting Ying, Kai Xu, Zhipeng Wu, Langhai Xu, Jisheng Ran, Weiping Chen, Lidong Wu
Summary: Osteoarthritis (OA) is an age-related disorder characterized by the loss of articular cartilage integrity. Mitochondrial dysfunction, particularly the downregulation of Lon protease 1 (LONP1), has been found to contribute to OA progression. This study revealed that decreased expression of LONP1 was associated with mitochondrial dysfunction, oxidative stress, metabolic changes, mitophagy, and MAPK pathway activation. Antioxidant therapy with resveratrol mitigated OA progression by suppressing oxidative stress and MAPK pathway activation induced by LONP1 knockdown.
FREE RADICAL BIOLOGY AND MEDICINE
(2022)
Article
Developmental Biology
Ke Zhao, Xinyi Huang, Wukui Zhao, Bin Lu, Zhongzhou Yang
Summary: This study reveals the importance of Lonp1 in mitochondrial quality control during heart development. Loss of Lonp1 leads to impaired heart development and embryonic lethality. Abnormalities in mitochondrial structure and protein aggregates are observed in Lonp1-deficient cardiomyocytes. Additionally, disruption of metabolic shifts and increased levels of reactive oxygen species are observed in Lonp1-deficient cells.
Article
Biochemistry & Molecular Biology
Karen Pollecker, Marc Sylvester, Wolfgang Voos
Summary: The mitochondrial matrix protease LONP1 plays a crucial role in organellar protein quality control system, respiration control, and apoptosis. Reduction in LONP1 level is associated with aging. A new cellular model system was established to study the impact of LONP1 on mitochondrial protein homeostasis using CRISPR/Cas-mediated genetic knockdown. The results suggest the applicability of the LONP1 gKD cell line as a model system for human aging processes, highlighting the important role of LONP1 in maintaining mitochondrial protein homeostasis in mammalian cells.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Cell Biology
Eirini Taouktsi, Eleni Kyriakou, Stefanos Smyrniotis, Fivos Borbolis, Labrina Bondi, Socratis Avgeris, Efstathios Trigazis, Stamatis Rigas, Gerassimos E. Voutsinas, Popi Syntichaki
Summary: Disruption of LonP1 leads to mitochondrial dysfunction and diverse cellular and organismal stress responses in both worms and cancer cells.
Article
Oncology
Laure Maneix, Melanie A. Sweeney, Sukyeong Lee, Polina Iakova, Shannon E. Moree, Ergun Sahin, Premal Lulla, Sarvari V. Yellapragada, Francis T. F. Tsai, Andre Catic
Summary: Multiple myeloma is the second most common cancer of the blood system in the US, with no effective cure currently available. The study shows that overexpression of the mitochondrial matrix protease LonP1 reduces the efficacy of proteasome inhibitors, potentially leading to drug resistance in multiple myeloma. Targeting both the proteasome and mitochondrial proteases like LonP1 could be beneficial for the treatment of this incurable cancer.
Article
Genetics & Heredity
Lu Qiao, Le Xu, Lan Yu, Julia Wynn, Rebecca Hernan, Xueya Zhou, Christiana Farkouh-Karoleski, Usha S. Krishnan, Julie Khlevner, Aliva De, Annette Zygmunt, Timothy Crombleholme, Foong-Yen Lim, Howard Needelman, Robert A. Cusick, George B. Mychaliska, Brad W. Warner, Amy J. Wagner, Melissa E. Danko, Dai Chung, Douglas Potoka, Przemyslaw Kosinski, David J. McCulley, Mahmoud Elfiky, Kenneth Azarow, Elizabeth Fialkowski, David Schindel, Samuel Z. Soffer, Jane B. Lyon, Jill M. Zalieckas, Badri N. Vardarajan, Gudrun Aspelund, Vincent P. Duron, Frances A. High, Xin Sun, Patricia K. Donahoe, Yufeng Shen, Wendy K. Chung
Summary: Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other anomalies. Studies have identified LONP1 and ALYREF as candidate CDH-associated genes, with implications for genetic studies of other congenital anomalies.
AMERICAN JOURNAL OF HUMAN GENETICS
(2021)
Article
Oncology
Yu Geon Lee, Hui Won Kim, Yeji Nam, Kyeong Jin Shin, Yu Jin Lee, Do Hong Park, Hyun-Woo Rhee, Jeong Kon Seo, Young Chan Chae
Summary: Mitochondrial proteases LONP1 and ClpP work together to alleviate proteotoxic stress and protect mitochondrial functions, supporting cancer cell survival. They target crucial components of mitochondrial functions and have overlapping substrates, such as SHMT2, to regulate cancer cell growth and sensitivity to metabolic stress. Patients with higher expression levels of LONP1 and ClpP have poorer prognosis in prostate cancer, suggesting that targeting the mitochondrial proteostasis network via these proteases could be a potential therapeutic strategy.
Review
Biochemistry & Molecular Biology
Haozhen Ma, Wanting Chen, Wenguo Fan, Hongwen He, Fang Huang
Summary: LonP1 plays a central role in mitochondrial function and energy metabolism, and has been associated with tumors and developmental disorders; High expression of LonP1 in oral and maxillofacial tumors makes it a potential anticancer therapy target; Further research on LonP1-related diseases is crucial for understanding LonP1-associated oral phenotypes and their molecular mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Environmental Sciences
Shulin Shan, Zhidan Liu, Shuai Wang, Zhaoxiong Liu, Shihua Chao, Cuiqin Zhang, Ming Li, Fuyong Song
Summary: This study found that mitochondrial oxidative stress regulates LonP1-TDP-43 pathway during CCl4-induced liver fibrosis. Targeting this pathway might serve as a promising therapeutic strategy for CCl4 exposure-induced liver diseases, as it can mitigate mitochondrial damage and prevent fibrosis.
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
(2023)
Review
Biochemistry & Molecular Biology
Maria Falkenberg
MITOCHONDRIAL DISEASES
(2018)
Article
Biochemistry & Molecular Biology
Thomas J. Nicholls, Cristina A. Nadalutti, Elisa Motori, Ewen W. Sommerville, Grainne S. Gorman, Swaraj Basu, Emily Hoberg, Doug M. Turnbull, Patrick F. Chinnery, Nils-Goran Larsson, Erik Larsson, Maria Falkenberg, Robert W. Taylor, Jack D. Griffith, Claes M. Gustafsson
Article
Multidisciplinary Sciences
Stanka Matic, Min Jiang, Thomas J. Nicholls, Jay P. Uhler, Caren Dirksen-Schwanenland, Paola Loguercio Polosa, Marie-Lune Simard, Xinping Li, Ilian Atanassov, Oliver Rackham, Aleksandra Filipovska, James B. Stewart, Maria Falkenberg, Nils-Goeran Larsson, Dusanka Milenkovic
NATURE COMMUNICATIONS
(2018)
Article
Biochemistry & Molecular Biology
Ali Al-Behadili, Jay P. Uhler, Anna-Karin Berglund, Bradley Peter, Mara Doimo, Aurelio Reyes, Sjoerd Wanrooij, Massimo Zeviani, Maria Falkenberg
NUCLEIC ACIDS RESEARCH
(2018)
Article
Biochemistry & Molecular Biology
Bradley Peter, Geraldine Farge, Carlos Pardo-Hernandez, Stefan Tangefjord, Maria Falkenberg
HUMAN MOLECULAR GENETICS
(2019)
Article
Genetics & Heredity
Viktor Posse, Ali Al-Behadili, Jay P. Uhler, Anders R. Clausen, Aurelio Reyes, Massimo Zeviani, Maria Falkenberg, Claes M. Gustafsson
Review
Biochemistry & Molecular Biology
Maria Falkenberg, Claes M. Gustafsson
CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2020)
Article
Clinical Neurology
Carola Hedberg-Oldfors, Ulrika Lindgren, Swaraj Basu, Kittichate Visuttijai, Christopher Lindberg, Maria Falkenberg, Erik Larsson Lekholm, Anders Oldfors
Summary: Deep sequencing and quantitation of mtDNA variants in muscle samples from IBM patients and controls revealed significantly increased levels of large deletions and duplications in IBM muscles, as well as indications of increased somatic single nucleotide variants and reduced mtDNA copy numbers compared to controls. The distribution and types of variants were similar in IBM muscle and controls, suggesting an accelerated aging process in IBM muscle possibly associated with chronic inflammation.
Article
Biochemistry & Molecular Biology
Meenakshi Singh, Viktor Posse, Bradley Peter, Maria Falkenberg, Claes M. Gustafsson
Summary: This study demonstrates that misincorporated ribonucleotides (rNMPs) in human mitochondrial genome can affect mitochondrial transcription, especially when they are present in consecutive stretches. This finding suggests that impaired transcription may be associated with genetic disorders characterized by imbalanced nucleotide pools and higher levels of embedded rNMPs.
NUCLEIC ACIDS RESEARCH
(2022)
Review
Cell Biology
Benedict G. Tan, Claes M. Gustafsson, Maria Falkenberg
Summary: This review discusses the regulation of gene expression in mitochondria and the initiation of transcription and replication in mitochondrial DNA (mtDNA) in human cells. The authors describe how different layers of regulation collaborate to fine-tune mtDNA transcription and replication, and how mtDNA packaging into nucleoids controls its accessibility and function.
NATURE REVIEWS MOLECULAR CELL BIOLOGY
(2023)