bims-nenemi 2024-09-15 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2024‒09‒15
eight papers selected by
Marco Tigano, Thomas Jefferson University

Mitochondrial RNA cytosolic leakage drives the SASP.
Variant load of mitochondrial DNA in single human mesenchymal stem cells.
Mitochondrial STED Imaging and Membrane Potential Monitoring with a Cationic Molecular Probe.
Targeting APT2 improves MAVS palmitoylation and antiviral innate immunity.
Visualizing mitochondrial dynamics at the nanoscale.
Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.
Role of Mitochondrial Dysfunctions in Neurodegenerative Disorders: Advances in Mitochondrial Biology.
CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism.

Res Sq. 2024 Aug 27. pii: rs.3.rs-4876596. [Epub ahead of print]

Mitochondrial RNA cytosolic leakage drives the SASP.

Stella Victorelli, Madeline Eppard, Seung-Hwa Woo, Stacia Everts, Helene Martini, Nicholas Pirius, Ana Catarina Franco, Yeaeun Han, Dominik Saul, Patrick Splinter, Steven O'Hara, Lucia Valenzuela-Pérez, Hyun Se Kim Lee, Diana Jurk, Nicholas LaRusso, Petra Hirsova, Joao Passos.

Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK plays a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction Associated Steatohepatitis (MASH). These findings highlight mtRNA's role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.

DOI: https://doi.org/10.21203/rs.3.rs-4876596/v1
Sci Rep. 2024 09 09. 14(1): 20989

Variant load of mitochondrial DNA in single human mesenchymal stem cells.

Daniel Hipps, Angela Pyle, Anna L R Porter, Philip F Dobson, Helen Tuppen, Conor Lawless, Oliver M Russell, Doug M Turnbull, David J Deehan, Gavin Hudson.

  Heteroplasmic mitochondrial DNA (mtDNA) variants accumulate as humans age, particularly in the stem-cell compartments, and are an important contributor to age-related disease. Mitochondrial dysfunction has been observed in osteoporosis and somatic mtDNA pathogenic variants have been observed in animal models of osteoporosis. However, this has never been assessed in the relevant human tissue. Mesenchymal stem cells (MSCs) are the progenitors to many cells of the musculoskeletal system and are critical to skeletal tissues and bone vitality. Investigating mtDNA in MSCs could provide novel insights into the role of mitochondrial dysfunction in osteoporosis. To determine if this is possible, we investigated the landscape of somatic mtDNA variation in MSCs through a combination of fluorescence-activated cell sorting and single-cell next-generation sequencing. Our data show that somatic heteroplasmic variants are present in individual patient-derived MSCs, can reach high heteroplasmic fractions and have the potential to be pathogenic. The identification of somatic heteroplasmic variants in MSCs of patients highlights the potential for mitochondrial dysfunction to contribute to the pathogenesis of osteoporosis.

Keywords:  Bone disease; Mesenchymal stem cells; Osteoporosis; Somatic mtDNA variation

DOI:  https://doi.org/10.1038/s41598-024-71822-4
Small Methods. 2024 Sep 13. e2400525

Mitochondrial STED Imaging and Membrane Potential Monitoring with a Cationic Molecular Probe.

Lu Gao, Rana Dalapati, Beibei Gao, Xiaoyu Huang, Dan Zhao, Fu Wang, Ling Zang.

  Mitochondria are essential organelles that not only undergo dynamic morphological changes but also exhibit functional activities such as mitochondrial membrane potential (MMP). While super-resolution techniques such as stimulated emission depletion (STED) nanoscopy can visualize the ultrastructure of mitochondria and the MMP probe can monitor mitochondria function, few dyes meet both demands. Here, a small molecule (MitoPDI-90) based on perylene diimide with cationic groups is reported and used for mitochondrial STED imaging and MMP indication. Characterized by excellent photostability, biocompatibility, and high quantum yield, MitoPDI-90 exhibits STED imaging compatibility, facilitating visualization of mitochondrial cristae and time-lapse imaging of highly dynamic mitochondria in living cells. Besides, MitoPDI-90 targets the mitochondria through electrical potential, also enabling live-cell MMP monitoring. MitoPDI-90 allows for super-resolution visualization and time-lapse imaging of mitochondria, and more importantly, indication of changes in MMP, providing insight into the functional activity of live-cell mitochondria.

Keywords:  STED microscopy; cationic molecular; cristae; mitochondrial membrane potential

DOI:  https://doi.org/10.1002/smtd.202400525
Mol Cell. 2024 Sep 06. pii: S1097-2765(24)00668-3. [Epub ahead of print]

Targeting APT2 improves MAVS palmitoylation and antiviral innate immunity.

Lang Bu, Huan Wang, Shuishen Zhang, Yi Zhang, Miaowen Liu, Zhengkun Zhang, Xueji Wu, Qiwei Jiang, Lei Wang, Wei Xie, Miao He, Zhengran Zhou, Chao Cheng, Jianping Guo.

  Innate immunity serves as the primary defense against viral and microbial infections in humans. The precise influence of cellular metabolites, especially fatty acids, on antiviral innate immunity remains largely elusive. Here, through screening a metabolite library, palmitic acid (PA) has been identified as a key modulator of antiviral infections in human cells. Mechanistically, PA induces mitochondrial antiviral signaling protein (MAVS) palmitoylation, aggregation, and subsequent activation, thereby enhancing the innate immune response. The palmitoyl-transferase ZDHHC24 catalyzes MAVS palmitoylation, thereby boosting the TBK1-IRF3-interferon (IFN) pathway, particularly under conditions of PA stimulation or high-fat-diet-fed mouse models, leading to antiviral immune responses. Additionally, APT2 de-palmitoylates MAVS, thus inhibiting antiviral signaling, suggesting that its inhibitors, such as ML349, effectively reverse MAVS activation in response to antiviral infections. These findings underscore the critical role of PA in regulating antiviral innate immunity through MAVS palmitoylation and provide strategies for enhancing PA intake or targeting APT2 for combating viral infections.

Keywords:  APT2; MAVS; ZDHHC24; innate immunity; palmitoylation

DOI:  https://doi.org/10.1016/j.molcel.2024.08.014
Light Sci Appl. 2024 Sep 09. 13(1): 244

Visualizing mitochondrial dynamics at the nanoscale.

Till Stephan, Peter Ilgen, Stefan Jakobs.

The study of mitochondria is a formidable challenge for super-resolution microscopy due to their dynamic nature and complex membrane architecture. In this issue, Ren et al. introduce HBmito Crimson, a fluorogenic and photostable mitochondrial probe for STED microscopy and investigate how mitochondrial dynamics influence the spatial organization of mitochondrial DNA.

DOI: https://doi.org/10.1038/s41377-024-01582-3
EMBO J. 2024 Sep 11.

Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.

Hilda Delgado de la Herran, Denis Vecellio Reane, Yiming Cheng, Máté Katona, Fabian Hosp, Elisa Greotti, Jennifer Wettmarshausen, Maria Patron, Hermine Mohr, Natalia Prudente de Mello, Margarita Chudenkova, Matteo Gorza, Safal Walia, Michael Sheng-Fu Feng, Anja Leimpek, Dirk Mielenz, Natalia S Pellegata, Thomas Langer, György Hajnóczky, Matthias Mann, Marta Murgia, Fabiana Perocchi.

  The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.

Keywords:  Calcium Signaling; Mitochondria; Mitochondrial Calcium Uniporter; Organelle; Proteomics

DOI:  https://doi.org/10.1038/s44318-024-00219-w
Mol Neurobiol. 2024 Sep 13.

Role of Mitochondrial Dysfunctions in Neurodegenerative Disorders: Advances in Mitochondrial Biology.

Divya Sri Kathiresan, Rubadevi Balasubramani, Kamalesh Marudhachalam, Piyush Jaiswal, Nivedha Ramesh, Suruthi Gunna Sureshbabu, Vinayaga Moorthi Puthamohan, Murali Vijayan.

  Mitochondria, essential organelles responsible for cellular energy production, emerge as a key factor in the pathogenesis of neurodegenerative disorders. This review explores advancements in mitochondrial biology studies that highlight the pivotal connection between mitochondrial dysfunctions and neurological conditions such as Alzheimer's, Parkinson's, Huntington's, ischemic stroke, and vascular dementia. Mitochondrial DNA mutations, impaired dynamics, and disruptions in the ETC contribute to compromised energy production and heightened oxidative stress. These factors, in turn, lead to neuronal damage and cell death. Recent research has unveiled potential therapeutic strategies targeting mitochondrial dysfunction, including mitochondria targeted therapies and antioxidants. Furthermore, the identification of reliable biomarkers for assessing mitochondrial dysfunction opens new avenues for early diagnosis and monitoring of disease progression. By delving into these advancements, this review underscores the significance of understanding mitochondrial biology in unraveling the mechanisms underlying neurodegenerative disorders. It lays the groundwork for developing targeted treatments to combat these devastating neurological conditions.

Keywords:  Biogenesis; Mitochondria; MtDNA dynamics; Neurodegeneration; Oxidative stress; Therapeutics

DOI:  https://doi.org/10.1007/s12035-024-04469-x
bioRxiv. 2024 Aug 31. pii: 2024.08.30.610586. [Epub ahead of print]

CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism.

Szu-Chi Liao, Kohei Kano, Sadhna Phanse, Mai Nguyen, Elyssa Margolis, YuHong Fu, Jonathan Meng, Mohamed Taha Moutaoufik, Zac Chatterton, Hiroyuki Aoki, Jeffrey Simms, Ivy Hsieh, Felecia Suteja, Yoshitaka Sei, Eric J Huang, Kevin McAvoy, Giovanni Manfredi, Glenda Halliday, Mohan Babu, Ken Nakamura.

Mutations in the mitochondrial cristae protein CHCHD2 lead to a late-onset autosomal dominant form of Parkinson's disease (PD) which closely resembles idiopathic PD, providing the opportunity to gain new insights into the mechanisms of mitochondrial dysfunction contributing to PD. To begin to address this, we used CRISPR genome-editing to generate CHCHD2 T61I point mutant mice. CHCHD2 T61I mice had normal viability, and had only subtle motor deficits with no signs of premature dopaminergic (DA) neuron degeneration. Nonetheless, CHCHD2 T61I mice exhibited robust molecular changes in the brain including increased CHCHD2 insolubility, accumulation of CHCHD2 protein preferentially in the substantia nigra (SN), and elevated levels of α-synuclein. Metabolic analyses revealed an increase in glucose metabolism through glycolysis relative to the TCA cycle with increased respiratory exchange ratio, and immune-electron microscopy revelated disrupted mitochondria in DA neurons. Moreover, spatial genomics revealed decreased expression of mitochondrial complex I and III respiratory chain proteins, while proteomics revealed increased respiratory chain and other mitochondrial protein-protein interactions. As such, the CHCHD2 T61I point-mutation mice exhibit robust mitochondrial disruption and a consequent metabolic shift towards glycolysis. These findings thus establish CHCHD2 T61I mice as a new model for mitochondrial-based PD, and implicate disrupted respiratory chain function as a likely causative driver.

DOI: https://doi.org/10.1101/2024.08.30.610586