bims-nenemi 2023-08-06 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2023–08–06
seventeen papers selected by
Marco Tigano, Thomas Jefferson University

Contact sites between endoplasmic reticulum sheets and mitochondria regulate mitochondrial DNA replication and segregation.
cGAS-STING drives ageing-related inflammation and neurodegeneration.
Central role of Tim17 in mitochondrial presequence protein translocation.
Inter-tissue communication of mitochondrial stress and metabolic health.
Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.
The role of mtDAMPs in the trauma-induced systemic inflammatory response syndrome.
MAVS Antagonizes Human Stem Cell Senescence as a Mitochondrial Stabilizer.
Cardiolipin-mediated temporal response to hydroquinone toxicity in human retinal pigmented epithelial cell line.
Nanoscale details of mitochondrial constriction revealed by cryo-electron tomography.
Decreased MFN2 activates the cGAS-STING pathway in diabetic myocardial ischaemia-reperfusion by triggering the release of mitochondrial DNA.
Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.
Inosine enhances tumor mitochondrial respiration by inducing Rag GTPases and nascent protein synthesis under nutrient starvation.
FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.
Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.
Plausible Role of Mitochondrial DNA Copy Number in Neurodegeneration-a Need for Therapeutic Approach in Parkinson's Disease (PD).
Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression.
Inhibition of mitochondrial fission and protein kinase R improves progesterone in placental stress.

iScience. 2023 Jul 21. 26(7): 107180

Contact sites between endoplasmic reticulum sheets and mitochondria regulate mitochondrial DNA replication and segregation.

Hema Saranya Ilamathi, Sara Benhammouda, Amel Lounas, Khalid Al-Naemi, Justine Desrochers-Goyette, Matthew A Lines, François J Richard, Jackie Vogel, Marc Germain.

  Mitochondria are multifaceted organelles crucial for cellular homeostasis that contain their own genome. Mitochondrial DNA (mtDNA) replication is a spatially regulated process essential for the maintenance of mitochondrial function, its defect causing mitochondrial diseases. mtDNA replication occurs at endoplasmic reticulum (ER)-mitochondria contact sites and is affected by mitochondrial dynamics: The absence of mitochondrial fusion is associated with mtDNA depletion whereas loss of mitochondrial fission causes the aggregation of mtDNA within abnormal structures termed mitobulbs. Here, we show that contact sites between mitochondria and ER sheets, the ER structure associated with protein synthesis, regulate mtDNA replication and distribution within mitochondrial networks. DRP1 loss or mutation leads to modified ER sheets and alters the interaction between ER sheets and mitochondria, disrupting RRBP1-SYNJ2BP interaction. Importantly, mtDNA distribution and replication were rescued by promoting ER sheets-mitochondria contact sites. Our work identifies the role of ER sheet-mitochondria contact sites in regulating mtDNA replication and distribution.

Keywords:  Biochemistry; Biological sciences; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2023.107180
Nature. 2023 Aug 02.

cGAS-STING drives ageing-related inflammation and neurodegeneration.

Muhammet F Gulen, Natasha Samson, Alexander Keller, Marius Schwabenland, Chong Liu, Selene Glück, Vivek V Thacker, Lucie Favre, Bastien Mangeat, Lona J Kroese, Paul Krimpenfort, Marco Prinz, Andrea Ablasser.

Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease1. Multiple factors can contribute to ageing-associated inflammation2; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA3, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.

DOI: https://doi.org/10.1038/s41586-023-06373-1
Nature. 2023 Aug 01.

Central role of Tim17 in mitochondrial presequence protein translocation.

Laura F Fielden, Jakob D Busch, Sandra G Merkt, Iniyan Ganesan, Conny Steiert, Hanna B Hasselblatt, Jon V Busto, Christophe Wirth, Nicole Zufall, Sibylle Jungbluth, Katja Noll, Julia M Dung, Ludmila Butenko, Karina von der Malsburg, Hans-Georg Koch, Carola Hunte, Martin van der Laan, Nils Wiedemann.

The presequence translocase of the mitochondrial inner membrane (TIM23) represents the major route for the import of nuclear-encoded proteins into mitochondria1,2. About 60% of more than 1,000 different mitochondrial proteins are synthesised with amino-terminal targeting signals, termed presequences, which form positively charged amphiphilic α-helices3,4. TIM23 sorts the presequence proteins into the inner membrane or matrix. Various views including regulatory and coupling functions have been reported on the essential TIM23 subunit Tim175-7. We mapped the interaction of Tim17 with matrix-targeted and inner membrane-sorted preproteins during translocation in the native membrane environment. We show that Tim17 contains conserved negative charges close to the intermembrane space side of the bilayer, which are essential to initiate presequence protein translocation along a distinct transmembrane cavity of Tim17 for both classes of preproteins. The amphiphilic character of mitochondrial presequences directly matches this Tim17-dependent translocation mechanism. This mechanism permits direct lateral release of transmembrane segments of inner membrane-sorted precursors into the inner membrane.

DOI: https://doi.org/10.1038/s41586-023-06477-8
Life Metab. 2023 Feb;pii: load001. [Epub ahead of print]2(1):

Inter-tissue communication of mitochondrial stress and metabolic health.

Hanlin Zhang, Xinyu Li, Wudi Fan, Sentibel Pandovski, Ye Tian, Andrew Dillin.

  Mitochondria function as a hub of the cellular metabolic network. Mitochondrial stress is closely associated with aging and a variety of diseases, including neurodegeneration and cancer. Cells autonomously elicit specific stress responses to cope with mitochondrial stress to maintain mitochondrial homeostasis. Interestingly, mitochondrial stress responses may also be induced in a non-autonomous manner in cells or tissues that are not directly experiencing such stress. Such non-autonomous mitochondrial stress responses are mediated by secreted molecules called mitokines. Due to their significant translational potential in improving human metabolic health, there has been a surge in mitokine-focused research. In this review, we summarize the findings regarding inter-tissue communication of mitochondrial stress in animal models. In addition, we discuss the possibility of mitokine-mediated intercellular mitochondrial communication originating from bacterial quorum sensing.

Keywords:  inter-tissue communication; metabolic health; mitochondria; mitokine; quorum sensing

DOI:  https://doi.org/10.1093/lifemeta/load001
EMBO Mol Med. 2023 Aug 03. e17399

Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.

Arpita Chowdhury, Angela Boshnakovska, Abhishek Aich, Aditi Methi, Ana Maria Vergel Leon, Ivan Silbern, Christian Lüchtenborg, Lukas Cyganek, Jan Prochazka, Radislav Sedlacek, Jiri Lindovsky, Dominic Wachs, Zuzana Nichtova, Dagmar Zudova, Gizela Koubkova, André Fischer, Henning Urlaub, Britta Brügger, Dörthe M Katschinski, Jan Dudek, Peter Rehling.

  Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid-driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V . Treatment of mutant cells with AMPK activator reestablishes fatty acid-driven OXPHOS and protects mice against cardiac dysfunction.

Keywords:  Barth syndrome; cardiolipin; cardiomyopathy; mitochondria; tafazzin

DOI:  https://doi.org/10.15252/emmm.202317399
Front Immunol. 2023 ;14 1164187

The role of mtDAMPs in the trauma-induced systemic inflammatory response syndrome.

Jingjing Ye, Xiaodan Hu, Zhiwei Wang, Rui Li, Lebin Gan, Mengwei Zhang, Tianbing Wang.

  Systemic inflammatory response syndrome (SIRS) is a non-specific exaggerated defense response caused by infectious or non-infectious stressors such as trauma, burn, surgery, ischemia and reperfusion, and malignancy, which can eventually lead to an uncontrolled inflammatory response. In addition to the early mortality due to the "first hits" after trauma, the trauma-induced SIRS and multiple organ dysfunction syndrome (MODS) are the main reasons for the poor prognosis of trauma patients as "second hits". Unlike infection-induced SIRS caused by pathogen-associated molecular patterns (PAMPs), trauma-induced SIRS is mainly mediated by damage-associated molecular patterns (DAMPs) including mitochondrial DAMPs (mtDAMPs). MtDAMPs released after trauma-induced mitochondrial injury, including mitochondrial DNA (mtDNA) and mitochondrial formyl peptides (mtFPs), can activate inflammatory response through multiple inflammatory signaling pathways. This review summarizes the role and mechanism of mtDAMPs in the occurrence and development of trauma-induced SIRS.

Keywords:  mtDAMPs; mtDNA; mtFPs; trauma; trauma-induced SIRS

DOI:  https://doi.org/10.3389/fimmu.2023.1164187
Research (Wash D C). 2023 ;6 0192

MAVS Antagonizes Human Stem Cell Senescence as a Mitochondrial Stabilizer.

Cui Wang, Kuan Yang, Xiaoqian Liu, Si Wang, Moshi Song, Juan Carlos Izpisua Belmonte, Jing Qu, Guang-Hui Liu, Weiqi Zhang.

Mitochondrial dysfunction is a hallmark feature of cellular senescence and organ aging. Here, we asked whether the mitochondrial antiviral signaling protein (MAVS), which is essential for driving antiviral response, also regulates human stem cell senescence. To answer this question, we used CRISPR/Cas9-mediated gene editing and directed differentiation techniques to generate various MAVS-knockout human stem cell models. We found that human mesenchymal stem cells (hMSCs) were sensitive to MAVS deficiency, as manifested by accelerated senescence phenotypes. We uncovered that the role of MAVS in maintaining mitochondrial structural integrity and functional homeostasis depends on its interaction with the guanosine triphosphatase optic atrophy type 1 (OPA1). Depletion of MAVS or OPA1 led to the dysfunction of mitochondria and cellular senescence, whereas replenishment of MAVS or OPA1 in MAVS-knockout hMSCs alleviated mitochondrial defects and premature senescence phenotypes. Taken together, our data underscore an uncanonical role of MAVS in safeguarding mitochondrial homeostasis and antagonizing human stem cell senescence.

DOI: https://doi.org/10.34133/research.0192
Biochim Biophys Acta Mol Cell Res. 2023 Jul 29. pii: S0167-4889(23)00127-1. [Epub ahead of print] 119554

Cardiolipin-mediated temporal response to hydroquinone toxicity in human retinal pigmented epithelial cell line.

Magdalena Davidescu, Letizia Mezzasoma, Katia Fettucciari, Luisa Pascucci, Marilena Pariano, Alessandro Di Michele, Oxana Bereshchenko, Carlo Cagini, Barbara Cellini, Lanfranco Corazzi, Ilaria Bellezza, Lara Macchioni.

  Hydroquinone, a potent toxic agent of cigarette smoke, damages retinal pigmented epithelial cells by triggering oxidative stress and mitochondrial dysfunction, two events causally related to the development and progression of retinal diseases. The inner mitochondrial membrane is enriched in cardiolipin, a phospholipid susceptible of oxidative modifications which determine cell-fate decision. Using ARPE-19 cell line as a model of retinal pigmented epithelium, we analyzed the potential involvement of cardiolipin in hydroquinone toxicity. Hydroquinone exposure caused an early concentration-dependent increase in mitochondrial reactive oxygen species, decrease in mitochondrial membrane potential, and rise in the rate of oxygen consumption not accompanied by changes in ATP levels. Despite mitochondrial impairment, cell viability was preserved. Hydroquinone induced cardiolipin translocation to the outer mitochondrial membrane, and an increase in the colocalization of the autophagosome adapter protein LC3 with mitochondria, indicating the induction of protective mitophagy. A prolonged hydroquinone treatment induced pyroptotic cell death by cardiolipin-mediated caspase-1 and gasdermin-D activation. Cardiolipin-specific antioxidants counteracted hydroquinone effects pointing out that cardiolipin can act as a mitochondrial "eat-me signal" or as a pyroptotic cell death trigger. Our results indicate that cardiolipin may act as a timer for the mitophagy to pyroptosis switch and propose cardiolipin-targeting compounds as promising approaches for the treatment of oxidative stress-related retinal diseases.

Keywords:  Cardiolipin; MTP-131; Mitochondria; Mitophagy; Pyroptosis; SkQ1

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119554
Biophys J. 2023 Aug 01. pii: S0006-3495(23)00481-2. [Epub ahead of print]

Nanoscale details of mitochondrial constriction revealed by cryo-electron tomography.

Shrawan Kumar Mageswaran, Danielle Ann Grotjahn, Xiangrui Zeng, Benjamin Asher Barad, Michaela Medina, My Hanh Hoang, Megan J Dobro, Yi-Wei Chang, Min Xu, Wei Yuan Yang, Grant J Jensen.

Mitochondria adapt to changing cellular environments, stress stimuli, and metabolic demands through dramatic morphological remodeling of their shape, and thus function. Such mitochondrial dynamics is often dependent on cytoskeletal filament interactions. However, the precise organization of these filamentous assemblies remains speculative. Here, we apply cryogenic electron tomography to directly image the nanoscale architecture of the cytoskeletal-membrane interactions involved in mitochondrial dynamics in response to damage. We induced mitochondrial damage via membrane depolarization, a cellular stress associated with mitochondrial fragmentation and mitophagy. We find that, in response to acute membrane depolarization, mammalian mitochondria predominantly organize into tubular morphology that abundantly displays constrictions. We observe long bundles of both unbranched actin and septin filaments enriched at these constrictions. We also observed septin-microtubule interactions at these sites and elsewhere suggesting that these two filaments guide each other in the cytosolic space. Together, our results provide empirical parameters for the architecture of mitochondrial constriction factors to validate/refine existing models and inform the development of new ones.

DOI: https://doi.org/10.1016/j.bpj.2023.07.030
Cell Commun Signal. 2023 Aug 03. 21(1): 192

Decreased MFN2 activates the cGAS-STING pathway in diabetic myocardial ischaemia-reperfusion by triggering the release of mitochondrial DNA.

Yonghong Xiong, Yan Leng, Hao Tian, Xinqi Deng, Wenyuan Li, Wei Li, Zhongyuan Xia.

   BACKGROUND: The cause of aggravation of diabetic myocardial damage is yet to be elucidated; damage to mitochondrial function has been a longstanding focus of research. During diabetic myocardial ischaemia-reperfusion (MI/R), it remains unclear whether reduced mitochondrial fusion exacerbates myocardial injury by generating free damaged mitochondrial DNA (mitoDNA) and activating the cGAS-STING pathway.
METHODS: In this study, a mouse model of diabetes was established (by feeding mice a high-fat diet (HFD) plus a low dose of streptozotocin (STZ)), a MI/R model was established by cardiac ischaemia for 2 h and reperfusion for 30 min, and a cellular model of glycolipid toxicity induced by high glucose (HG) and palmitic acid (PA) was established in H9C2 cells.
RESULTS: We observed that altered mitochondrial dynamics during diabetic MI/R led to increased mitoDNA in the cytosol, activation of the cGAS-STING pathway, and phosphorylation of the downstream targets TBK1 and IRF3. In the cellular model we found that cytosolic mitoDNA was the result of reduced mitochondrial fusion induced by HG and PA, which also resulted in cGAS-STING signalling and activation of downstream targets. Moreover, inhibition of STING by H-151 significantly ameliorated myocardial injury induced by MFN2 knockdown in both the cell and mouse models. The use of a fat-soluble antioxidant CoQ10 improved cardiac function in the mouse models.
CONCLUSIONS: Our study elucidated the critical role of cGAS-STING activation, triggered by increased cytosolic mitoDNA due to decreased mitochondrial fusion, in the pathogenesis of diabetic MI/R injury. This provides preclinical insights for the treatment of diabetic MI/R injury. Video Abstract.

Keywords:  Diabetes; Mitochondrial DNA; Myocardial ischaemia–reperfusion; cGAS-STING

DOI:  https://doi.org/10.1186/s12964-023-01216-y
J Cell Biol. 2023 Oct 02. pii: e202303147. [Epub ahead of print]222(10):

Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.

Olivia M Connor, Srujan K Matta, Jonathan R Friedman.

Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by a dynamin-related protein, Dnm1 (Drp1 in humans), that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity is sufficient to complete the fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1 (also named Atg44). Loss of Mdi1 causes mitochondrial hyperfusion due to defects in fission, but not the lack of Dnm1 recruitment to mitochondria. Mdi1 is conserved in fungal species, and its homologs contain an amphipathic α-helix, mutations of which disrupt mitochondrial morphology. One model is that Mdi1 distorts mitochondrial membranes to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of Mdi1 inside mitochondria.

DOI: https://doi.org/10.1083/jcb.202303147
Cell Death Dis. 2023 Aug 02. 14(8): 492

Inosine enhances tumor mitochondrial respiration by inducing Rag GTPases and nascent protein synthesis under nutrient starvation.

Mei-Xin Li, Xiao-Ting Wu, Wen-Qiang Jing, Wen-Kui Hou, Sheng Hu, Wei Yan.

Metabolic heterogeneity of tumor microenvironment (TME) is a hallmark of cancer and a big barrier to cancer treatment. Cancer cells display diverse capacities to utilize alternative carbon sources, including nucleotides, under poor nutrient circumstances. However, whether and how purine, especially inosine, regulates mitochondrial metabolism to buffer nutrient starvation has not been well-defined yet. Here, we identify the induction of 5'-nucleotidase, cytosolic II (NT5C2) gene expression promotes inosine accumulation and maintains cancer cell survival in the nutrient-poor region. Inosine elevation further induces Rag GTPases abundance and mTORC1 signaling pathway by enhancing transcription factor SP1 level in the starved tumor. Besides, inosine supplementary stimulates the synthesis of nascent TCA cycle enzymes, including citrate synthesis (CS) and aconitase 1 (ACO1), to further enhance oxidative phosphorylation of breast cancer cells under glucose starvation, leading to the accumulation of iso-citric acid. Inhibition of the CS activity or knockdown of ACO1 blocks the rescue effect of inosine on cancer survival under starvation. Collectively, our finding highlights the vital signal role of inosine linking mitochondrial respiration and buffering starvation, beyond serving as direct energy carriers or building blocks for genetic code in TME, shedding light on future cancer treatment by targeting inosine metabolism.

DOI: https://doi.org/10.1038/s41419-023-06017-2
PLoS Biol. 2023 Aug 03. 21(8): e3002244

FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.

Alvaro Sanchez-Martinez, Aitor Martinez, Alexander J Whitworth.

Functional analyses of genes linked to heritable forms of Parkinson's disease (PD) have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations in PARK15/FBXO7 cause autosomal recessive PD and FBXO7 has been shown to regulate mitochondrial homeostasis. We investigated the extent to which FBXO7 and its Drosophila orthologue, ntc, share functional homology and explored its role in mitophagy in vivo. We show that ntc mutants partially phenocopy Pink1 and parkin mutants and ntc overexpression supresses parkin phenotypes. Furthermore, ntc can modulate basal mitophagy in a Pink1- and parkin-independent manner by promoting the ubiquitination of mitochondrial proteins, a mechanism that is opposed by the deubiquitinase USP30. This basal ubiquitination serves as the substrate for Pink1-mediated phosphorylation that triggers stress-induced mitophagy. We propose that FBXO7/ntc works in equilibrium with USP30 to provide a checkpoint for mitochondrial quality control in basal conditions in vivo and presents a new avenue for therapeutic approaches.

DOI: https://doi.org/10.1371/journal.pbio.3002244
Cell Death Dis. 2023 Aug 03. 14(8): 496

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.

Volha Liaudanskaya, Nicholas J Fiore, Yang Zhang, Yuka Milton, Marilyn F Kelly, Marly Coe, Ariana Barreiro, Victoria K Rose, Matthew R Shapiro, Adam S Mullis, Anna Shevzov-Zebrun, Mathew Blurton-Jones, Michael J Whalen, Aviva J Symes, Irene Georgakoudi, Thomas J F Nieland, David L Kaplan.

Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.

DOI: https://doi.org/10.1038/s41419-023-05980-0
Mol Neurobiol. 2023 Jul 31.

Plausible Role of Mitochondrial DNA Copy Number in Neurodegeneration-a Need for Therapeutic Approach in Parkinson's Disease (PD).

Dhivya Venkatesan, Mahalaxmi Iyer, Arul Narayanasamy, Abilash Valsala Gopalakrishnan, Balachandar Vellingiri.

  Parkinson's disease (PD) is an advancing age-associated progressive brain disorder which has various diverse factors, among them mitochondrial dysfunction involves in dopaminergic (DA) degeneration. Aging causes a rise in mitochondrial abnormalities which leads to structural and functional modifications in neuronal activity and cell death in PD. This ends in deterioration of mitochondrial function, mitochondrial alterations, mitochondrial DNA copy number (mtDNA CN) and oxidative phosphorylation (OXPHOS) capacity. mtDNA levels or mtDNA CN in PD have reported that mtDNA depletion would be a predisposing factor in PD pathogenesis. To maintain the mtDNA levels, therapeutic approaches have been focused on mitochondrial biogenesis in PD. The depletion of mtDNA levels in PD can be influenced by autophagic dysregulation, apoptosis, neuroinflammation, oxidative stress, sirtuins, and calcium homeostasis. The current review describes the regulation of mtDNA levels and discusses the plausible molecular pathways in mtDNA CN depletion in PD pathogenesis. We conclude by suggesting further research on mtDNA depletion which might show a promising effect in predicting and diagnosing PD.

Keywords:  Copy number; Mitochondrial DNA; Molecular pathways; Parkinson’s disease; TFAM; Therapeutic strategies

DOI:  https://doi.org/10.1007/s12035-023-03500-x
Cell Death Differ. 2023 Aug 04.

Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression.

Emily Van San, Angela C Debruyne, Geraldine Veeckmans, Yulia Y Tyurina, Vladimir A Tyurin, Hao Zheng, Sze Men Choi, Koen Augustyns, Geert van Loo, Bernhard Michalke, Vivek Venkataramani, Shinya Toyokuni, Hülya Bayir, Peter Vandenabeele, Behrouz Hassannia, Tom Vanden Berghe.

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by central nervous (CNS) demyelination resulting in axonal injury and neurological deficits. Essentially, MS is driven by an auto-amplifying mechanism of inflammation and cell death. Current therapies mainly focus on disease modification by immunosuppression, while no treatment specifically focuses on controlling cell death injury. Here, we report that ferroptosis, an iron-catalyzed mode of regulated cell death (RCD), contributes to MS disease progression. Active and chronic MS lesions and cerebrospinal fluid (CSF) of MS patients revealed several signs of ferroptosis, reflected by the presence of elevated levels of (labile) iron, peroxidized phospholipids and lipid degradation products. Treatment with our candidate lead ferroptosis inhibitor, UAMC-3203, strongly delays relapse and ameliorates disease progression in a preclinical model of relapsing-remitting MS. In conclusion, the results identify ferroptosis as a detrimental and targetable factor in MS. These findings create novel treatment options for MS patients, along with current immunosuppressive strategies.

DOI: https://doi.org/10.1038/s41418-023-01195-0
J Mol Endocrinol. 2023 Jul 01. pii: JME-23-0059. [Epub ahead of print]

Inhibition of mitochondrial fission and protein kinase R improves progesterone in placental stress.

Umut Kerem KolaÇ.

Placenta synthesizes hormones that play a vital role in adapting maternal physiology and supporting fetal growth. This study aimed to explore the link between progesterone, a key steroid hormone produced by placenta, and mitochondrial fission and protein kinase R through use of chemical inhibition in trophoblasts subjected to endotoxin lipopolysaccharide and double-stranded RNA analog polyinosinic-polycytidylic acid stress. Expressions of protein kinase R, dynamin related protein1, mitochondrial fission protein1 and heat shock protein 60 were determined by applying lipopolysaccharide and polyinosinic-polycytidylic acid to BeWo trophoblast cells. Next, cells were treated with protein kinase R inhibitor 2-aminopurine and mitochondrial division inhibitor1 to examine changes in progesterone levels and expression levels of proteins and mRNAs involved in progesterone biosynthesis. Last, effect of 2-aminopurine on mitochondrial fission was determined by immunoblotting and qPCR. Mitochondrial structural changes were also examined by transmission electron microscopy. Lipopolysaccharide and polyinosinic-polycytidylic acid stimulation induced mitochondrial fission, activated protein kinase R but decreased heat shock protein 60 levels and progesterone synthesis. Chemical inhibition of mitochondrial fission elevated progesterone synthesis and protein and mRNA levels of genes involved in progesterone biosynthesis. Inhibition of protein kinase R with 2-aminopurine prevented lipopolysaccharide and polyinosinic-polycytidylic acid induced mitochondrial fission and increased progesterone biosynthesis. Use of chemical inhibitors to treat placental stress caused by pathogens has potential to stabilize the production of progesterone. The study reveals that inhibiting mitochondrial fragmentation and reducing activity of stress kinase protein kinase R in syncytiotrophoblasts leads to an increase in progesterone synthesis when exposed to lipopolysaccharide and polyinosinic-polycytidylic acid.

DOI: https://doi.org/10.1530/JME-23-0059