bims-nenemi 2022-01-23 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2022–01–23
23 papers selected by
Marco Tigano, Thomas Jefferson University

FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury.
The portrait of liver cancer is shaped by mitochondrial genetics.
Mitochondrial protein import and UPRmt in skeletal muscle remodeling and adaptation.
Impact of ER Stress and ER-Mitochondrial Crosstalk in Huntington's Disease.
Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas.
DRAM-4 and DRAM-5 are compensatory regulators of autophagy and cell survival in nutrient-deprived conditions.
Mitochondrial oxidative stress mediated Fe-induced ferroptosis via the NRF2-ARE pathway.
Mitochondrial DNA copy number and disease.
Sensing of RNA stress by mTORC1 drives autoinflammation.
BRAF Inhibitors Reprogram Cancer-Associated Fibroblasts to Drive Matrix Remodeling and Therapeutic Escape in Melanoma.
Nuclear and mitochondrial DNA editing in human cells with zinc finger deaminases.
Mitochondria-mediated oxidative stress during viral infection.
Testing Mitochondrial-Targeted Drugs in iPSC-RPE from Patients with Age-Related Macular Degeneration.
CXCL12/CXCR4 axis supports mitochondrial trafficking in tumor myeloma microenvironment.
Cellular senescence: all roads lead to mitochondria.
The mitochondrial anti-apoptotic dependencies of hematological malignancies: from disease biology to advances in precision medicine.
Golgi anti-apoptotic proteins redundantly counteract cell death by inhibiting production of reactive oxygen species under endoplasmic reticulum stress.
NAD supplementation improves mitochondrial performance of cardiolipin mutants.
NEAT1 Confers Radioresistance to Hepatocellular Carcinoma Cells by Inducing Autophagy through GABARAP.
Mitophagy-regulated mitochondrial health strongly protects the heart against cardiac dysfunction after acute myocardial infarction.
PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes.
Role of systems biology and multi-omics analyses in delineating spatial interconnectivity and temporal dynamicity of ER stress mediated cellular responses.
Mechanisms associated with the dysregulation of mitochondrial function due to lead exposure and possible implications on the development of Alzheimer's disease.

Cell Signal. 2022 Jan 17. pii: S0898-6568(22)00009-2. [Epub ahead of print] 110249

FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury.

Haizhe Ji, Jin Wang, David Muid, Wei Song, Yinong Jiang, Hao Zhou.

  The mitochondrial unfolded protein response (UPRmt) is an adaptive transcriptional response involving the activation of proteases, chaperones, and antioxidant enzymes and serves to degrade abnormal or unfolded proteins and restore mitochondrial function. Although the cardioprotective action of the UPRmt has been verified in myocardial ischemia/reperfusion (I/R) injuries, the upstream signals involved remain unclear. Here, we explored the regulatory mechanisms underlying UPRmt in the reperfused mouse heart. UPRmt was slightly activated by I/R injury. UPRmt activation (using oligomycin) and inhibition (with the protease inhibitor AEBSF) respectively alleviated and augmented the reperfusion-mediated myocardial damage. Gene expression analysis demonstrated that oxidative stress was partly inhibited by UPRmt through upregulation of mitochondria-localized, not cytoplasmic, antioxidant enzymes. Contributing to cardiomyocyte survival under I/R, the transcription of pro-apoptotic proteins Bcl2 and c-IAP was also stimulated by UPRmt. Moreover, UPRmt upregulated mitochondrial fusion-related, but not fission-related, genes and stimulated the expression of mitochondrial biogenesis markers in reperfused hearts. Finally, we found that FUN14 domain containing 1 (FUNDC1)-mediated mitophagy induces the mitochondrial DNA decrease, triggering UPRmt. These results demonstrate that FUNDC1 functions upstream of the UPRmt to maintain mitochondrial quality control during myocardial I/R injury.

Keywords:  Cardiomyocyte; FUNDC1; Mitochondrial unfolded protein response; Mitophagy; Myocardial I/R injury

DOI:  https://doi.org/10.1016/j.cellsig.2022.110249
Cell Rep. 2022 Jan 18. pii: S2211-1247(21)01766-6. [Epub ahead of print]38(3): 110254

The portrait of liver cancer is shaped by mitochondrial genetics.

Mrittika Chattopadhyay, Edmund Charles Jenkins, Ana Victoria Lechuga-Vieco, Kai Nie, Maria Isabel Fiel, Alexander Rialdi, Ernesto Guccione, Jose Antonio Enriquez, Daniela Sia, Amaia Lujambio, Doris Germain.

  Cancer heterogeneity and evolution are not fully understood. Here, we show that mitochondrial DNA of the normal liver shapes tumor progression, histology, and immune environment prior to the acquisition of oncogenic mutation. Using conplastic mice, we show that mtDNA dictates the expression of the mitochondrial unfolded protein response (UPRmt) in the normal liver. Activation of oncogenic mutations in UPRmt-positive liver increases tumor incidence and histological heterogeneity. Further, in a subset of UPRmt-positive mice, invasive liver cancers develop. RNA sequencing (RNA-seq) analysis of the normal liver reveals that, in this subset, the PAPP-A/DDR2/SNAIL axis of invasion pre-exists along with elevated collagen. Since PAPP-A promotes immune evasion, we analyzed the immune signature and found that their livers are immunosuppressed. Further, the PAPP-A signature identifies the immune exhausted subset of hepatocellular carcinoma (HCC) in humans. Our data suggest that mtDNA of normal liver shapes the entire liver cancer portrait upon acquisition of oncogenic mutations.

Keywords:  DDR2; PAPP-A; UPRmt; collagen; conplastic mice; estrogen receptor; immune exhausted; liver cancer; mitochondrial UPR; sexual dimorphism

DOI:  https://doi.org/10.1016/j.celrep.2021.110254
Semin Cell Dev Biol. 2022 Jan 18. pii: S1084-9521(22)00004-0. [Epub ahead of print]

Mitochondrial protein import and UPRmt in skeletal muscle remodeling and adaptation.

Brandon J Richards, Mikhaela Slavin, Ashley N Oliveira, Victoria C Sanfrancesco, David A Hood.

  The biogenesis of mitochondria requires the coordinated expression of the nuclear and the mitochondrial genomes. However, the vast majority of gene products within the organelle are encoded in the nucleus, synthesized in the cytosol, and imported into mitochondria via the protein import machinery, which permit the entry of proteins to expand the mitochondrial network. Once inside, proteins undergo a maturation and folding process brought about by enzymes comprising the unfolded protein response (UPRmt). Protein import and UPRmt activity must be synchronized and matched with mtDNA-encoded subunit synthesis for proper assembly of electron transport chain complexes to avoid proteotoxicity. This review discusses the functions of the import and UPRmt systems in mammalian skeletal muscle, as well as how exercise alters the equilibrium of these pathways in a time-dependent manner, leading to a new steady state of mitochondrial content resulting in enhanced oxidative capacity and improved muscle health.

Keywords:  Adaptation; Exercise; Mitochondrial biogenesis; Protein folding; Protein import machinery; Proteostasis

DOI:  https://doi.org/10.1016/j.semcdb.2022.01.002
Int J Mol Sci. 2022 Jan 11. pii: 780. [Epub ahead of print]23(2):

Impact of ER Stress and ER-Mitochondrial Crosstalk in Huntington's Disease.

Shuvadeep Maity, Pragya Komal, Vaishali Kumar, Anshika Saxena, Ayesha Tungekar, Vaani Chandrasekar.

  Accumulation of misfolded proteins is a common phenomenon of several neurodegenerative diseases. The misfolding of proteins due to abnormal polyglutamine (PolyQ) expansions are linked to the development of PolyQ diseases including Huntington's disease (HD). Though the genetic basis of PolyQ repeats in HD remains prominent, the primary molecular basis mediated by PolyQ toxicity remains elusive. Accumulation of misfolded proteins in the ER or disruption of ER homeostasis causes ER stress and activates an evolutionarily conserved pathway called Unfolded protein response (UPR). Protein homeostasis disruption at organelle level involving UPR or ER stress response pathways are found to be linked to HD. Due to dynamic intricate connections between ER and mitochondria, proteins at ER-mitochondria contact sites (mitochondria associated ER membranes or MAMs) play a significant role in HD development. The current review aims at highlighting the most updated information about different UPR pathways and their involvement in HD disease progression. Moreover, the role of MAMs in HD progression has also been discussed. In the end, the review has focused on the therapeutic interventions responsible for ameliorating diseased states via modulating either ER stress response proteins or modulating the expression of ER-mitochondrial contact proteins.

Keywords:  ER; ER stress; Huntington’s disease (HD); mitochondria; mitochondria associated ER membranes (MAM)

DOI:  https://doi.org/10.3390/ijms23020780
Cancers (Basel). 2022 Jan 06. pii: 269. [Epub ahead of print]14(2):

Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas.

Mouna Tabebi, Małgorzata Łysiak, Ravi Kumar Dutta, Sandra Lomazzi, Maria V Turkina, Laurent Brunaud, Oliver Gimm, Peter Söderkvist.

   BACKGROUND: Somatic mutations, copy-number variations, and genome instability of mitochondrial DNA (mtDNA) have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is scarce information about pheochromocytomas and paragangliomas (PCCs/PGLs) formation.
MATERIAL: To determine the potential roles of mtDNA alterations in sporadic PCCs/PGLs, we analyzed a panel of 26 nuclear susceptibility genes and the entire mtDNA sequence of seventy-seven human tumors, using next-generation sequencing, and compared the results with normal adrenal medulla tissues. We also performed an analysis of copy-number alterations, large mtDNA deletion, and gene and protein expression.
RESULTS: Our results revealed that 53.2% of the tumors harbor a mutation in at least one of the targeted susceptibility genes, and 16.9% harbor complementary mitochondrial mutations. More than 50% of the mitochondrial mutations were novel and predicted pathogenic, affecting mitochondrial oxidative phosphorylation. Large deletions were found in 26% of tumors, and depletion of mtDNA occurred in more than 87% of PCCs/PGLs. The reduction of the mitochondrial number was accompanied by a reduced expression of the regulators that promote mitochondrial biogenesis (PCG1α, NRF1, and TFAM). Further, P62 and LC3a gene expression suggested increased mitophagy, which is linked to mitochondrial dysfunction.
CONCLUSION: The pathogenic role of these finding remains to be shown, but we suggest a complementarity and a potential contributing role in PCCs/PGLs tumorigenesis.

Keywords:  genetic alterations; mitochondrial DNA; pheochromocytomas and paragangliomas

DOI:  https://doi.org/10.3390/cancers14020269
FEBS J. 2022 Jan 21.

DRAM-4 and DRAM-5 are compensatory regulators of autophagy and cell survival in nutrient-deprived conditions.

Valentin J A Barthet, Michaela Mrschtik, Elzbieta Kania, David G McEwan, Dan Croft, James O'Prey, Jaclyn S Long, Kevin M Ryan.

Macroautophagy is a membrane-trafficking process that delivers cytoplasmic material to lysosomes for degradation. The process preserves cellular integrity by removing damaged cellular constituents and can promote cell survival by providing substrates for energy production during hiatuses of nutrient availability. The process is also highly responsive to other forms of cellular stress. For example, DNA damage can induce autophagy and this involves up-regulation of the Damage-Regulated Autophagy Modulator-1 (DRAM-1) by the tumor suppressor p53. DRAM-1 belongs to an evolutionarily-conserved protein family, which has five members in humans and we describe here the initial characterization of two members of this family, which we term DRAM-4 and DRAM-5 for DRAM-Related/Associated Member 4/5. We show that the genes encoding these proteins are not regulated by p53, but instead are induced by nutrient deprivation. Similar to other DRAM family proteins, however, DRAM-4 principally localizes to endosomes and DRAM-5 to the plasma membrane and both modulate autophagy flux when over-expressed. Deletion of DRAM-4 using CRISPR/Cas-9 also increased autophagy flux, but we found that DRAM-4 and DRAM-5 undergo compensatory regulation, such that deletion of DRAM-4 does not affect autophagy flux in the absence of DRAM-5. Similarly, deletion of DRAM-4 also promotes cell survival following growth of cells in the absence of amino acids, serum or glucose, but this effect is also impacted by the absence of DRAM-5. In summary, DRAM-4 and DRAM-5 are nutrient-responsive members of the DRAM family that exhibit interconnected roles in the regulation of autophagy and cell survival under nutrient-deprived conditions.

DOI: https://doi.org/10.1111/febs.16365
Free Radic Biol Med. 2022 Jan 16. pii: S0891-5849(22)00023-5. [Epub ahead of print]180 95-107

Mitochondrial oxidative stress mediated Fe-induced ferroptosis via the NRF2-ARE pathway.

Guang-Hui Chen, Chang-Chun Song, Kostas Pantopoulos, Xiao-Lei Wei, Hua Zheng, Zhi Luo.

  Ferroptosis is a regulated form of cell death induced by iron (Fe)-dependent lipid peroxidation. At present, the underlying molecular mechanisms remain elusive. Herein, we hypothesized that mitochondria and the NRF2 (transcription factor nuclear factor E2-related factor 2) are potential mediators of ferroptosis, considering their well-established involvement in the oxidative stress pathway. We found that a high iron diet increased hepatic iron content and promoted glutathione (GSH) depletion, lipid peroxidation and oxidative stress. Dietary iron overload also decreased mRNA and protein expression levels of glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11), and increased mRNA and protein expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), which are all markers of ferroptosis. Consistent with ferroptosis, iron overload promoted lipid peroxidation and the generation of mitochondrial reactive oxygen species (ROS), and decreased the mitochondrial membrane potential (MMP). Pre-treatment with deferoxamine mesylate (DFO, an iron chelator) alleviated ROS generation and lipid peroxidation, indicating a causative link between iron overload and lipid peroxidation. Suppression of mitochondrial oxidative stress attenuated ferroptosis. Experiments with HEK293T cells revealed that Fe-induced ferroptosis involved direct inhibition of NRF2 binding to antioxidant response elements (AREs) within the promoters of the gpx4 and slc7a11 genes, which in turn induced transcriptional silencing. In conclusion, our study provided a direct link between mitochondrial oxidative stress and ferroptosis via the NRF2-ARE pathway.

Keywords:  Ferroptosis; Iron overload; Mitochondrial dysfunction; Oxidative stress; Vertebrates

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.01.012
Nat Rev Genet. 2022 Jan 21.

Mitochondrial DNA copy number and disease.

Dorothy Clyde.

DOI: https://doi.org/10.1038/s41576-022-00451-2
J Clin Invest. 2022 Jan 18. pii: e156119. [Epub ahead of print]132(2):

Sensing of RNA stress by mTORC1 drives autoinflammation.

Min Ae Lee-Kirsch.

Loss-of-function mutations in SKIV2L underlie trichohepatoenteric syndrome (THES2), a rare inborn error of immunity characterized by diarrhea, skin lesions, brittle hair, and immunodeficiency. SKIV2L is part of a multiprotein complex required for exosome-mediated RNA surveillance through RNA decay. In this issue of the JCI, Yang et al. delineate a mechanism underlying autoinflammatory skin disease in Skiv2l-deficient mice. Thus, a lack of SKIV2L activates mTORC1 signaling in keratinocytes and T cells, impeding skin barrier integrity and T cell homeostasis. Interestingly, treatment with the mTOR inhibitor rapamycin improves skin symptoms in Skiv2l-deficient mice, suggesting a possible therapeutic avenue for patients with THES2.

DOI: https://doi.org/10.1172/JCI156119
Cancer Res. 2022 Jan 21.

BRAF Inhibitors Reprogram Cancer-Associated Fibroblasts to Drive Matrix Remodeling and Therapeutic Escape in Melanoma.

Tianyi Liu, Linli Zhou, Yao Xiao, Thomas Andl, Yuhang Zhang.

The tumor stroma and its cellular components are known to play an important role in tumor response to treatment. Here, we report a novel resistance mechanism in melanoma that is elicited by BRAF inhibitor (BRAFi)-induced noncanonical activation of nuclear β-catenin signaling in cancer-associated fibroblasts (CAF). Treatment with BRAFi leads to an expanded CAF population with increased β-catenin nuclear accumulation and enhanced biological properties. This CAF subpopulation is essential for melanoma cells to proliferate and acquire resistance to BRAFi/MEK inhibitors (MEKi). Mechanistically, BRAFi induces BRAF-CRAF heterodimerization and subsequent activation of ERK signaling in CAFs, leading to inactivation of the β-catenin destruction complex. RNA-seq identified periostin (POSTN) as a major downstream effector of β-catenin in CAFs. POSTN compensates for the loss of β-catenin in CAFs and mediates melanoma cell BRAFi/MEKi resistance. In melanoma cells, POSTN activates phosphoinositide 3-kinase (PI3K)/AKT signaling and subsequently reactivates the ERK pathway that was inhibited by BRAFi/MEKi. Collectively, these data underscore the role of BRAFi-induced CAF reprogramming in matrix remodeling and therapeutic escape of melanoma cells. SIGNIFICANCE: β-Catenin activation in cancer-associated fibroblasts in response to BRAF inhibitors stimulates POSTN secretion to promote resistance in cancer cells, revealing POSTN as a potential matrix target in cancer therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-0614
Nat Commun. 2022 Jan 18. 13(1): 366

Nuclear and mitochondrial DNA editing in human cells with zinc finger deaminases.

Kayeong Lim, Sung-Ik Cho, Jin-Soo Kim.

Base editing in nuclear DNA and mitochondrial DNA (mtDNA) is broadly useful for biomedical research, medicine, and biotechnology. Here, we present a base editing platform, termed zinc finger deaminases (ZFDs), composed of custom-designed zinc-finger DNA-binding proteins, the split interbacterial toxin deaminase DddAtox, and a uracil glycosylase inhibitor (UGI), which catalyze targeted C-to-T base conversions without inducing unwanted small insertions and deletions (indels) in human cells. We assemble plasmids encoding ZFDs using publicly available zinc finger resources to achieve base editing at frequencies of up to 60% in nuclear DNA and 30% in mtDNA. Because ZFDs, unlike CRISPR-derived base editors, do not cleave DNA to yield single- or double-strand breaks, no unwanted indels caused by error-prone non-homologous end joining are produced at target sites. Furthermore, recombinant ZFD proteins, expressed in and purified from E. coli, penetrate cultured human cells spontaneously to induce targeted base conversions, demonstrating the proof-of-principle of gene-free gene therapy.

DOI: https://doi.org/10.1038/s41467-022-27962-0
Trends Microbiol. 2022 Jan 18. pii: S0966-842X(21)00318-8. [Epub ahead of print]

Mitochondria-mediated oxidative stress during viral infection.

Jonathan Foo, Gregory Bellot, Shazib Pervaiz, Sylvie Alonso.

  Through oxidative phosphorylation, mitochondria play a central role in energy production and are an important production source of reactive oxygen species (ROS). Not surprisingly, viruses have evolved to exploit this organelle in order to support their infection cycle. Beyond its role in the cellular antiviral response, induction of oxidative stress has emerged as a common strategy employed by many viruses to promote their replication. Here, we review the key molecular mechanisms employed by viruses to interact with mitochondria and induce oxidative stress. Furthermore, we discuss how viruses benefit from increased ROS levels, how they control ROS production to maintain a favorable redox environment, and how they cope with ROS-mediated cell death.

Keywords:  antioxidant therapy; electron transport chain (ETC); endoplasmic reticulum (ER) stress; intrinsic apoptosis; oxidative phosphorylation (OXPHOS); reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.tim.2021.12.011
Pharmaceuticals (Basel). 2022 Jan 04. pii: 62. [Epub ahead of print]15(1):

Testing Mitochondrial-Targeted Drugs in iPSC-RPE from Patients with Age-Related Macular Degeneration.

Mara C Ebeling, Zhaohui Geng, Madilyn R Stahl, Rebecca J Kapphahn, Heidi Roehrich, Sandra R Montezuma, Deborah A Ferrington, James R Dutton.

  Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. No universally effective treatments exist for atrophic or "dry" AMD, which results from loss of the retinal pigment epithelium (RPE) and photoreceptors and accounts for ≈80% of all AMD patients. Prior studies provide evidence for the involvement of mitochondrial dysfunction in AMD pathology. This study used induced pluripotent stem cell (iPSC) RPE derived from five AMD patients to test the efficacy of three drugs (AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), Metformin, trehalose) that target key processes in maintaining optimal mitochondrial function. The patient iPSC-RPE lines were used in a proof-of-concept drug screen, utilizing an analysis of RPE mitochondrial function following acute and extended drug exposure. Results show considerable variability in drug response across patient cell lines, supporting the need for a personalized medicine approach for treating AMD. Furthermore, our results demonstrate the feasibility of using iPSC-RPE from AMD patients to develop a personalized drug treatment regime and provide a roadmap for the future clinical management of AMD.

Keywords:  age-related macular degeneration; human-induced pluripotent stem cells; personalized drug testing; retinal pigment epithelium

DOI:  https://doi.org/10.3390/ph15010062
Oncogenesis. 2022 Jan 21. 11(1): 6

CXCL12/CXCR4 axis supports mitochondrial trafficking in tumor myeloma microenvironment.

Cesarina Giallongo, Ilaria Dulcamare, Daniele Tibullo, Vittorio Del Fabro, Nunzio Vicario, Nunziatina Parrinello, Alessandra Romano, Grazia Scandura, Giacomo Lazzarino, Concetta Conticello, Giovanni Li Volti, Angela Maria Amorini, Giuseppe Musumeci, Michelino Di Rosa, Francesca Polito, Rosaria Oteri, M'hammed Aguennouz, Rosalba Parenti, Francesco Di Raimondo, Giuseppe A Palumbo.

Mesenchymal stromal cells (MSCs) within the protective microenvironment of multiple myeloma (MM) promote tumor growth, confer chemoresistance and support metabolic needs of plasma cells (PCs) even transferring mitochondria. In this scenario, heterocellular communication and dysregulation of critical signaling axes are among the major contributors to progression and treatment failure. Here, we report that myeloma MSCs have decreased reliance on mitochondrial metabolism as compared to healthy MSCs and increased tendency to deliver mitochondria to MM cells, suggesting that this intercellular exchange between PCs and stromal cells can be consider part of MSC pro-tumorigenic phenotype. Interestingly, we also showed that PCs promoted expression of connexin 43 (CX43) in MSCs leading to CXCL12 activation and stimulation of its receptor CXCR4 on MM cells favoring protumor mitochondrial transfer. Consistently, we observed that selective inhibition of CXCR4 by plerixafor resulted in a significant reduction of mitochondria trafficking. Moreover, intracellular expression of CXCR4 in myeloma PCs from BM biopsy specimens demonstrated higher CXCR4 colocalization with CD138+ cells of non-responder patients to bortezomib compared with responder patients, suggesting that CXCR4 mediated chemoresistance in MM. Taken together, our data demonstrated that CXCL12/CXCR4 axis mediates intercellular coupling thus suggesting that the myeloma niche may be exploited as a target to improve and develop therapeutic approaches.

DOI: https://doi.org/10.1038/s41389-022-00380-z
FEBS J. 2022 Jan 20.

Cellular senescence: all roads lead to mitochondria.

Hélène Martini, João F Passos.

  Senescence is a multi-functional cell fate, characterized by an irreversible cell-cycle arrest and a pro-inflammatory phenotype, commonly known as the Senescence-Associated secretory Phenotype (SASP). Emerging evidence indicates that accumulation of senescent cells in multiple tissues, drives tissue dysfunction and several age-related conditions. This has spurred the academic community and industry to identify new therapeutic interventions targeting this process. Mitochondrial dysfunction is an often-unappreciated hallmark of cellular senescence which plays important roles not only in the senescence growth arrest but also in the development of the SASP and resistance to cell-death. Here, we review the evidence that supports a role for mitochondria in the development of senescence and describe the underlying mechanisms. Finally, we propose that a detailed road map of mitochondrial biology in senescence will be crucial to guide the future development of senotherapies.

Keywords:  Mitochondria; SASP; aging; senescence

DOI:  https://doi.org/10.1111/febs.16361
Haematologica. 2022 Jan 20.

The mitochondrial anti-apoptotic dependencies of hematological malignancies: from disease biology to advances in precision medicine.

Isacco Ferrarini, Antonella Rigo, Carlo Visco.

Mitochondria are critical organelles in the regulation of intrinsic apoptosis. As a general feature of blood cancers, different anti-apoptotic members of the BCL-2 protein family localize at the outer mitochondrial membrane to sequester variable amounts of pro-apoptotic activators, and hence protect cancer cells from death induction. However, the impact of distinct anti-apoptotic members on apoptosis prevention, a concept termed anti-apoptotic dependence, remarkably differs across disease entities. Over the last two decades, several genetic and functional methodologies have been established to uncover the anti-apoptotic dependencies of the majority of blood cancers, inspiring the development of a new class of small molecules called BH3 mimetics. In this review, we highlight the rationale of targeting mitochondrial apoptosis in hematology, and provide a comprehensive map of the antiapoptotic dependencies that are currently guiding novel therapeutic strategies. Cell-extrinsic and intrinsic mechanisms conferring resistance to BH3 mimetics are also examined, with insights on potential strategies to overcome them. We finally discuss how the field of mitochondrial apoptosis might be complemented with other dimensions of precision medicine for more successfully treating 'highly complex' hematological malignancies.

DOI: https://doi.org/10.3324/haematol.2021.280201
J Exp Bot. 2022 Jan 16. pii: erac011. [Epub ahead of print]

Golgi anti-apoptotic proteins redundantly counteract cell death by inhibiting production of reactive oxygen species under endoplasmic reticulum stress.

Xiao-Han Tang, Xin Li, Yan Zhou, Yu-Ting He, Zhi-Ying Wang, Xue Yang, Wei Wang, Kun Guo, Wei Zhang, Yue Sun, Hong-Qing Li, Xiao-Fang Li.

  Maintaining proteostasis in the endoplasmic reticulum (ER) is critical for the cell viability and plant survival under adverse conditions. The unfolded protein response (UPR) pathways interact with reactive oxygen species (ROS) to precisely trigger adaptive outputs or cell death under ER-stress with varying degrees. However, little information is known about how the relationship between the UPR signalling and ROS is regulated in plant. Here, Arabidopsis Golgi anti-apoptotic protein1 (GAAP1) to GAAP4 were found to play redundant positive roles against ER stress. Genetic analysis showed that GAAP4 played its role in IRE1-dependent and -independent pathways. In addition, GAAPs played negative function to activate the adaptive UPR in conditions of stress. Quantitative biochemical analysis showed that mutations in GAAPs genes decreased the oxidised glutathione level and altered the change pattern of ROS and glutathione in the early ER stress. When plants were challenged with unmitigated ER stress, mutations in GAAP advanced ROS accumulation, which was associated with a decline in adaptive UPR. These data indicated that GAAPs resist cell death at least by regulating glutathione to inhibit ROS accumulation and maintain UPR across ER stress. They provide basis for further analysis of the regulation of cell fate decision in ER stress.

Keywords:   Arabidopsis thaliana ; GAAPs; endoplasmic reticulum stress; glutathione; reactive oxygen species; unfolded protein response

DOI:  https://doi.org/10.1093/jxb/erac011
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Jan 17. pii: S1388-1981(21)00222-5. [Epub ahead of print] 159094

NAD supplementation improves mitochondrial performance of cardiolipin mutants.

Jiajia Ji, Deena Damschroder, Denise Bessert, Pablo Lazcano, Robert Wessells, Christian A Reynolds, Miriam L Greenberg.

  Cardiolipin (CL) deficiency causes mitochondrial dysfunction and aberrant metabolism that are associated in humans with the severe disease Barth syndrome (BTHS). Several metabolic abnormalities are observed in BTHS patients and model systems, including decreased oxidative phosphorylation, reduced tricarboxylic acid (TCA) cycle flux, and accumulated lactate and D-β-hydroxybutyrate, which strongly suggests that nicotinamide adenine dinucleotide (NAD) redox metabolism may be altered in CL-deficient cells. In this study, we identified abnormal NAD+ metabolism in multiple BTHS model systems and demonstrate that supplementation of NAD+ precursors such as nicotinamide mononucleotide (NMN) improves mitochondrial function. Improved mitochondrial function in the Drosophila model was associated with restored exercise endurance, which suggests a potential therapeutic benefit of NAD+ precursor supplementation in the management of BTHS patients.

Keywords:  Barth syndrome; Cardiolipin deficiency; Mitochondrial function; NAD(+) precursors; NAD(+) redox; Nicotinamide mononucleotide

DOI:  https://doi.org/10.1016/j.bbalip.2021.159094
Int J Mol Sci. 2022 Jan 10. pii: 711. [Epub ahead of print]23(2):

NEAT1 Confers Radioresistance to Hepatocellular Carcinoma Cells by Inducing Autophagy through GABARAP.

Hiromi Sakaguchi, Hiroyuki Tsuchiya, Yutaka Kitagawa, Tomohiko Tanino, Kenji Yoshida, Nobue Uchida, Goshi Shiota.

  A long noncoding RNA (lncRNA), nuclear enriched abundant transcript 1 (NEAT1) variant 1 (NEAT1v1), is involved in the maintenance of cancer stem cells (CSCs) in hepatocellular carcinoma (HCC). CSCs are suggested to play important roles in therapeutic resistance. Therefore, we investigated whether NEAT1v1 is involved in the sensitivity to radiation therapy in HCC. Gene knockdown was performed using short hairpin RNAs, and NEAT1v1-overexpressing HCC cell lines were generated by stable transfection with a NEAT1v1-expressing plasmid DNA. Cells were irradiated using an X-ray generator. We found that NEAT1 knockdown enhanced the radiosensitivity of HCC cell lines and concomitantly inhibited autophagy. NEAT1v1 overexpression enhanced autophagy in the irradiated cells and conferred radioresistance. Gamma-aminobutyric acid receptor-associated protein (GABARAP) expression was downregulated by NEAT1 knockdown, whereas it was upregulated in NEAT1v1-overexpressing cells. Moreover, GABARAP was required for NEAT1v1-induced autophagy and radioresistance as its knockdown significantly inhibited autophagy and sensitized the cells to radiation. Since GABARAP is a crucial protein for the autophagosome-lysosome fusion, our results suggest that NEAT1v1 confers radioresistance to HCC by promoting autophagy through GABARAP.

Keywords:  GABARAP; NEAT1; autophagy; hepatocellular carcinoma; long noncoding RNA; radioresistance

DOI:  https://doi.org/10.3390/ijms23020711
J Cell Mol Med. 2022 Jan 18.

Mitophagy-regulated mitochondrial health strongly protects the heart against cardiac dysfunction after acute myocardial infarction.

Chunling Xu, Yangpo Cao, Ruxia Liu, Lei Liu, Weilin Zhang, Xuan Fang, Shi Jia, Jingjing Ye, Yingying Liu, Lin Weng, Xue Qiao, Bo Li, Ming Zheng.

  Autophagy including mitophagy serves as an important regulatory mechanism in the heart to maintain the cellular homeostasis and to protect against heart damages caused by myocardial infarction (MI). The current study aims to dissect roles of general autophagy and specific mitophagy in regulating cardiac function after MI. By using Beclin1+/- , Fundc1 knockout (KO) and Fundc1 transgenic (TG) mouse models, combined with starvation and MI models, we found that Fundc1 KO caused more severe mitochondrial and cardiac dysfunction damages than Beclin1+/- after MI. Interestingly, Beclin1+/- caused notable decrease of total autophagy without detectable change to mitophagy, and Fundc1 KO markedly suppressed mitophagy but did not change the total autophagy activity. In contrast, starvation increased total autophagy without changing mitophagy while Fundc1 TG elevated total autophagy and mitophagy in mouse hearts. As a result, Fundc1 TG provided much stronger protective effects than starvation after MI. Moreover, Beclin1+/- /Fundc1 TG showed increased total autophagy and mitophagy to a level comparable to Fundc1 TG per se, and completely reversed Beclin1+/- -caused aggravation of mitochondrial and cardiac injury after MI. Our results reveal that mitophagy but not general autophagy contributes predominantly to the cardiac protective effect through regulating mitochondrial function.

Keywords:  Beclin1; Fundc1; acute myocardial infarction; autophagy; mitophagy

DOI:  https://doi.org/10.1111/jcmm.17190
Diabetes. 2022 Jan 14. pii: db210443. [Epub ahead of print]

PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes.

Bernat Elvira, Valerie Vandenbempt, Julia Bauzá-Martinez, Raphaël Crutzen, Javier Negueruela, Hazem Ibrahim, Matthew L Winder, Manoja K Brahma, Beata Vekeriotaite, Pieter-Jan Martens, Sumeet Pal Singh, Fernando Rossello, Pascale Lybaert, Timo Otonkoski, Conny Gysemans, Wei Wu, Esteban N Gurzov.

Type 1 diabetes (T1D) results from autoimmune destruction of β-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell dysfunction. Here, we assessed the global protein and individual PTP profiles in the pancreas from early onset non-obese diabetic (NOD) mice treated with an anti-CD3 monoclonal antibody and interleukin-1 receptor antagonist. The treatment reversed hyperglycemia and we observed enhanced expression of PTPN2, a PTP family member and T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the pancreatic islets. To address the functional role of PTPN2 in β-cells, we generated PTPN2-deficient human stem cell-derived β-like and EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates type I and type II interferon signaling networks and the potential progression towards autoimmunity. Moreover, we established the capacity of PTPN2 to positively modulate the Ca2+-dependent unfolded protein response and ER stress outcome in β-cells. Adenovirus-induced overexpression of PTPN2 partially protected from ER-stress induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes.

DOI: https://doi.org/10.2337/db21-0443
Biochim Biophys Acta Mol Cell Res. 2022 Jan 12. pii: S0167-4889(22)00001-5. [Epub ahead of print] 119210

Role of systems biology and multi-omics analyses in delineating spatial interconnectivity and temporal dynamicity of ER stress mediated cellular responses.

Priyanka Mallick, Sebabrata Maity, Oishee Chakrabarti, Saikat Chakrabarti.

  The endoplasmic reticulum (ER) is a membranous organelle involved in calcium storage, lipid biosynthesis, protein folding and processing. Many patho-physiological conditions and pharmacological agents are known to perturb normal ER function and can lead to ER stress, which severely compromise protein folding mechanism and hence poses high risk of proteotoxicity. Upon sensing ER stress, the different stress signaling pathways interconnect with each other and work together to preserve cellular homeostasis. ER stress response is a part of the integrative stress response (ISR) and might play an important role in the pathogenesis of chronic neurodegenerative diseases, where misfolded protein accumulation and cell death are common. The initiation, manifestation and progression of ER stress mediated unfolded protein response (UPR) is a complex procedure involving multiple proteins, pathways and cellular organelles. To understand the cause and consequences of such complex processes, implementation of an integrative holistic approach is required to identify novel players and regulators of ER stress. As multi-omics data-based systems analyses have shown potential to unravel the underneath molecular mechanism of complex biological systems, it is important to emphasize the utility of this approach in understanding the ER stress biology. In this review we first discuss the ER stress signaling pathways and regulatory players, along with their inter-connectivity. We next highlight the importance of systems and network biology approaches using multi-omics data in understanding ER stress mediated cellular responses. This report would help advance our current understanding of the multivariate spatial interconnectivity and temporal dynamicity of ER stress.

Keywords:  Endoplasmic reticulum stress; Multi-omics approaches; Stress sensing pathways; Unfolded protein response; meta-pathway network

DOI:  https://doi.org/10.1016/j.bbamcr.2022.119210
Biometals. 2022 Jan 20.

Mechanisms associated with the dysregulation of mitochondrial function due to lead exposure and possible implications on the development of Alzheimer's disease.

Lakshmi Jaya Madhuri Bandaru, Neelima Ayyalasomayajula, Lokesh Murumulla, Suresh Challa.

  Lead (Pb) is a multimedia contaminant with various pathophysiological consequences, including cognitive decline and neural abnormalities. Recent findings have reported an association of Pb toxicity with Alzheimer's disease (AD). Studies have revealed that mitochondrial dysfunction is a pathological characteristic of AD. According to toxicology reports, Pb promotes mitochondrial oxidative stress by lowering complex III activity in the electron transport chain, boosting reactive oxygen species formation, and reducing the cell's antioxidant defence system. Here, we review recent advances in the role of mitochondria in Pb-induced AD pathology, as well as the mechanisms associated with the mitochondrial dysfunction, such as the depolarisation of the mitochondrial membrane potential, mitochondrial permeability transition pore opening; mitochondrial biogenesis, bioenergetics and mitochondrial dynamics alterations; and mitophagy and apoptosis. We also discuss possible therapeutic options for mitochondrial-targeted neurodegenerative disease (AD).

Keywords:  Alzheimer’s disease; Lead toxicity; Mitochondrial dysfunction; Reactive oxygen species; β-Amyloid peptide

DOI:  https://doi.org/10.1007/s10534-021-00360-7