bims-minimp Biomed News
on Mitochondria, innate immunity, proteostasis
Issue of 2022‒07‒17
sixteen papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences
  1. The nuclear encoded Cox7c mRNA co-transport with mitochondria along axons via coding-region dependent mechanism.
  2. Mitochondrial Transfusion Improves Mitochondrial Function Through Up-regulation of Mitochondrial Complex II Protein Subunit SDHB in the Hippocampus of Aged Mice.
  3. Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling.
  4. Context-dependent roles of cellular senescence in normal, aged, and disease states.
  5. Hijacking Cellular Stress Responses to Promote Lifespan.
  6. IFN-Aging: Coupling Aging With Interferon Response.
  7. Decreasing pdzd8-mediated mito-ER contacts improves organismal fitness and mitigates Aβ42 toxicity.
  8. Selective pericentromeric heterochromatin dismantling caused by TP53 activation during senescence.
  9. Deletion of Letmd1 leads to the disruption of mitochondrial function in brown adipose tissue.
  10. The MitoAging Project: Single nucleotide polymorphisms (SNPs) in mitochondrial genes and their association to longevity.
  11. Tamoxifen modulates mitochondrial dynamics through AMPK and MAPK during nutrition deprivation.
  12. Mitochondrial prohibitin complex regulates fungal virulence via ATG24-assisted mitophagy.
  13. Altered Nutrient Uptake Causes Mitochondrial Dysfunction in Senescent CD8+ EMRA T Cells During Type 2 Diabetes.
  14. Heme oxygenase-1 protects against endotoxin-induced acute lung injury depends on NAD+-mediated mitonuclear communication through PGC1α/PPARγ signaling pathway.
  15. CHCHD2 maintains mitochondrial contact site and cristae organizing system stability and protects against mitochondrial dysfunction in an experimental model of Parkinson's disease.
  16. The mitochondrial translocator protein (TSPO): a key multifunctional molecule in the nervous system.
  1. J Cell Sci. 2022 Jul 14. pii: jcs.259436. [Epub ahead of print]
    The nuclear encoded Cox7c mRNA co-transport with mitochondria along axons via coding-region dependent mechanism.
    Bar Cohen, Topaz Altman, Adi Golani-Armon, Anca F Savulescu, Amjd Ibraheem, Musa M Mhlanga, Eran Perlson, Yoav S Arava.
      Nuclear encoded mitochondrial protein mRNAs have been found to be localized and locally translated within neuronal processes. However, the transport mechanism of those mRNAs to distal locations is not fully understood. Here, we describe axonal co-transport of Cox7c with mitochondria. Fractionation analysis and smFISH assay revealed that endogenous mRNA encoding Cox7c is preferentially associated with mitochondria from a neuronal cell line and within primary motor neuron axons, while other mRNAs, which do not encode mitochondrial protein are much less associated. Live cell imaging of MS2-tagged Cox7c mRNA further confirmed the preferential colocalization and co-transport of Cox7c mRNA with mitochondria in motor neuron axons. Intriguingly, the coding region, rather than the 3' UTR, was the key domain for the cotransport. Our results reveal that Cox7c mRNA can be transported with mitochondria along significant distances and its coding region is a major recognition feature. This is consistent with the idea that mitochondria can play a vital role in spatial regulation of the axonal transcriptome at distant neuronal sites.
    Keywords:  Axonal transport; Cox7c; Mitochondria; mRNA localization; mRNA transport
    DOI:  https://doi.org/10.1242/jcs.259436
  2. Mol Neurobiol. 2022 Jul 14.
    Mitochondrial Transfusion Improves Mitochondrial Function Through Up-regulation of Mitochondrial Complex II Protein Subunit SDHB in the Hippocampus of Aged Mice.
    A Adlimoghaddam, T Benson, B C Albensi.
      The mitochondrial theory of aging is characterized by mitochondrial electron transport chain dysfunction. As a hallmark of aging, an increasing number of investigations have attempted to improve mitochondrial function in both aging and age-related disease. Emerging from these attempts, methods involving mitochondrial isolation, transfusion, and transplantation have taken center stage. In particular, mitochondrial transfusion refers to the administration of mitochondria from healthy tissue into the bloodstream or into tissues affected by injury, disease, or aging. In this study, methods of mitochondrial isolation and transfusion were developed and utilized. First, we found a significant decrease (p < 0.05) in the expression of mitochondrial complex proteins (I-V) in aged (12 months old) mouse brain tissue (C57BL/6 mice) in comparison to healthy young brain tissue (1 month old). To investigate whether healthy young mitochondria taken from the liver could improve mitochondrial function in older animals, we intravenously injected mitochondria isolated from young C57BL/6 mice into aged mice from the same strain. This study, for the first time, demonstrates that mitochondrial transfusion significantly (p < 0.05) improves mitochondrial function via the up-regulation of the mitochondrial complex II protein subunit SDHB in the hippocampus of aged mice. This result has identified a role for mitochondrial complex II in the aging process. Therefore, mitochondrial complex II could serve as a putative target for therapeutic interventions against aging. However, more importantly, methods of mitochondrial transfusion should be further tested to treat a variety of human diseases or disorders and to slow down or reverse processes of aging.
    Keywords:  Age-related disease; Aging; Bioenergetics; Brain; Complex II; Mitochondrial dysfunction; Mitochondrial transfusion; Neuroscience
    DOI:  https://doi.org/10.1007/s12035-022-02937-w
  3. Immunity. 2022 Jul 07. pii: S1074-7613(22)00280-1. [Epub ahead of print]
    Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling.
    Hongxu Xian, Kosuke Watari, Elsa Sanchez-Lopez, Joseph Offenberger, Janset Onyuru, Harini Sampath, Wei Ying, Hal M Hoffman, Gerald S Shadel, Michael Karin.
      Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice.
    Keywords:  FEN1; NLRP3 inflammasome; OGG1; Ox-mtDNA; VDAC; cGAS-STING; mPTP; mitochondria; mtDNA
    DOI:  https://doi.org/10.1016/j.immuni.2022.06.007
  4. FEBS J. 2022 Jul 11.
    Context-dependent roles of cellular senescence in normal, aged, and disease states.
    Victoria Moiseeva, Andrés Cisneros, Aina Calls Cobos, Aida Beà Tarrega, Claudia Santos Oñate, Eusebio Perdiguero, Antonio L Serrano, Pura Muñoz-Cánoves.
      Cellular senescence is a state of irreversible cell cycle arrest that often emerges after tissue damage and in age-related diseases. Through the production of a multicomponent secretory phenotype (SASP), senescent cells can impact the regeneration and function of tissues. However, the effects of senescent cells and their SASP are very heterogeneous and depend on the tissue environment and type as well as the duration of injury, the degree of persistence of senescent cells, and the organism's age. While the transient presence of senescent cells is widely believed to be beneficial, recent data suggest that it is detrimental for tissue regeneration after acute damage. Further, although senescent cell persistence is typically associated with the progression of age-related chronic degenerative diseases, it now appears to be also necessary for correct tissue function in the elderly. Here, we discuss what is currently known about the roles of senescent cells and their SASP in tissue regeneration in aging and age-related diseases, highlighting their (negative and/or positive) contributions. We provide insight for future research, including the possibility of senolytic-based therapies and cellular reprogramming, with aims ranging from enhancing tissue repair to extending a healthy lifespan.
    Keywords:  SASP; Senescence; aging; disease; regeneration
    DOI:  https://doi.org/10.1111/febs.16573
  5. Front Aging. 2022 ;3 860404
    Hijacking Cellular Stress Responses to Promote Lifespan.
    Naibedya Dutta, Gilberto Garcia, Ryo Higuchi-Sanabria.
      Organisms are constantly exposed to stress both from the external environment and internally within the cell. To maintain cellular homeostasis under different environmental and physiological conditions, cell have adapted various stress response signaling pathways, such as the heat shock response (HSR), unfolded protein responses of the mitochondria (UPRMT), and the unfolded protein response of the endoplasmic reticulum (UPRER). As cells grow older, all cellular stress responses have been shown to deteriorate, which is a major cause for the physiological consequences of aging and the development of numerous age-associated diseases. In contrast, elevated stress responses are often associated with lifespan extension and amelioration of degenerative diseases in different model organisms, including C. elegans. Activating cellular stress response pathways could be considered as an effective intervention to alleviate the burden of aging by restoring function of essential damage-clearing machinery, including the ubiquitin-proteosome system, chaperones, and autophagy. Here, we provide an overview of newly emerging concepts of these stress response pathways in healthy aging and longevity with a focus on the model organism, C. elegans.
    Keywords:  C. elegans; aging; endoplasmic reticulum; heat-shock; mitochondria; stress
    DOI:  https://doi.org/10.3389/fragi.2022.860404
  6. Front Aging. 2022 ;3 870489
    IFN-Aging: Coupling Aging With Interferon Response.
    Wei Cao.
      Chronic inflammation affects many diseases and conditions, including aging. Interferons are a part of the immune defense against viral infections. Paradoxically, various aging tissues and organs from mammalian hosts perpetually accumulate changes brought by interferon pathway activation. Herein, we connote the mechanisms behind this phenomenon and discuss its implications in age-related pathology.
    Keywords:  aging; inflammaging; interferon; laminopathy; mitochondria; senescence; transposable elements
    DOI:  https://doi.org/10.3389/fragi.2022.870489
  7. Life Sci Alliance. 2022 Nov;pii: e202201531. [Epub ahead of print]5(11):
    Decreasing pdzd8-mediated mito-ER contacts improves organismal fitness and mitigates Aβ42 toxicity.
    Victoria L Hewitt, Leonor Miller-Fleming, Madeleine J Twyning, Simonetta Andreazza, Francesca Mattedi, Julien Prudent, Franck Polleux, Alessio Vagnoni, Alexander J Whitworth.
      Mitochondria-ER contact sites (MERCs) orchestrate many important cellular functions including regulating mitochondrial quality control through mitophagy and mediating mitochondrial calcium uptake. Here, we identify and functionally characterize the Drosophila ortholog of the recently identified mammalian MERC protein, Pdzd8. We find that reducing pdzd8-mediated MERCs in neurons slows age-associated decline in locomotor activity and increases lifespan in Drosophila. The protective effects of pdzd8 knockdown in neurons correlate with an increase in mitophagy, suggesting that increased mitochondrial turnover may support healthy aging of neurons. In contrast, increasing MERCs by expressing a constitutive, synthetic ER-mitochondria tether disrupts mitochondrial transport and synapse formation, accelerates age-related decline in locomotion, and reduces lifespan. Although depletion of pdzd8 prolongs the survival of flies fed with mitochondrial toxins, it is also sufficient to rescue locomotor defects of a fly model of Alzheimer's disease expressing Amyloid β42 (Aβ42). Together, our results provide the first in vivo evidence that MERCs mediated by the tethering protein pdzd8 play a critical role in the regulation of mitochondrial quality control and neuronal homeostasis.
    DOI:  https://doi.org/10.26508/lsa.202201531
  8. Nucleic Acids Res. 2022 Jul 12. pii: gkac603. [Epub ahead of print]
    Selective pericentromeric heterochromatin dismantling caused by TP53 activation during senescence.
    Aaron Mendez-Bermudez, Liudmyla Lototska, Melanie Pousse, Florent Tessier, Oliver Croce, Chrysa M Latrick, Veronica Cherdyntseva, Joe Nassour, Jiang Xiaohua, Yiming Lu, Corinne Abbadie, Sarantis Gagos, Jing Ye, Eric Gilson.
      Cellular senescence triggers various types of heterochromatin remodeling that contribute to aging. However, the age-related mechanisms that lead to these epigenetic alterations remain elusive. Here, we asked how two key aging hallmarks, telomere shortening and constitutive heterochromatin loss, are mechanistically connected during senescence. We show that, at the onset of senescence, pericentromeric heterochromatin is specifically dismantled consisting of chromatin decondensation, accumulation of DNA breakages, illegitimate recombination and loss of DNA. This process is caused by telomere shortening or genotoxic stress by a sequence of events starting from TP53-dependent downregulation of the telomere protective protein TRF2. The resulting loss of TRF2 at pericentromeres triggers DNA breaks activating ATM, which in turn leads to heterochromatin decondensation by releasing KAP1 and Lamin B1, recombination and satellite DNA excision found in the cytosol associated with cGAS. This TP53-TRF2 axis activates the interferon response and the formation of chromosome rearrangements when the cells escape the senescent growth arrest. Overall, these results reveal the role of TP53 as pericentromeric disassembler and define the basic principles of how a TP53-dependent senescence inducer hierarchically leads to selective pericentromeric dismantling through the downregulation of TRF2.
    DOI:  https://doi.org/10.1093/nar/gkac603
  9. Biochimie. 2022 Jul 08. pii: S0300-9084(22)00178-X. [Epub ahead of print]
    Deletion of Letmd1 leads to the disruption of mitochondrial function in brown adipose tissue.
    Runjie Song, Yaqi Du, Peng Li, Lijun Zhou, Han Zheng, Xiaohui Lu, Shenghong Wang, Wenqiang Ma, Hua Zhang, Xiangdong Li.
      Human cervical cancer oncogene (HCCR-1), also named as LETMD1, is an LETM-domain containing outer mitochondrial membrane protein which plays an important role in carcinogenesis. The present study found that the loss of Letmd1 in mice led to severe abnormities, such as brown adipose tissue (BAT) whitening, impaired thermogenesis of both BAT and beige fat, cold intolerance, diet-induced obesity, glucose intolerance and insulin resistance. Mechanically, the deletion of Letmd1 in BAT caused decreased level of both mitochondrial and intracellular Ca2+. The reduced intracellular Ca2+ could suppress the fission of mitochondria and ultimately lead to the disruption of BAT thermogenesis by regulating mitochondrial structures and functions. This study indicates that LETMD1 played a crucial role in BAT thermogenesis and energy homeostasis through regulating mitochondrial structures and functions, which provides a novel insight into therapeutic target exploration from oncogenes for metabolic disorders.
    Keywords:  Insulin resistance; LETMD1; Mitochondrial; Obesity; Thermogenesis; brown adipose tissue
    DOI:  https://doi.org/10.1016/j.biochi.2022.07.002
  10. Mitochondrion. 2022 Jul 08. pii: S1567-7249(22)00056-3. [Epub ahead of print]
    The MitoAging Project: Single nucleotide polymorphisms (SNPs) in mitochondrial genes and their association to longevity.
    Verónica Castañedaa, Alissen Haro-Vinueza, Ivonne Salinas, Andrés Caicedod, Miguel Angel Mendez.
      Mitochondrial dysfunction is a major hallmark of aging. Mitochondrial DNA (mtDNA) mutations (inherited or acquired) may cause a malfunction of the respiratory chain (RC), and thus negatively affect cell metabolism and function. In contrast, certain mtDNA single nucleotide polymorphisms (SNPs) may be beneficial to mitochondrial electron transport chain function and the extension of cellular health as well as lifespan. The goal of the MitoAging project is to detect key physiological characteristics and mechanisms that improve mitochondrial function and use them to develop therapies to increase longevity and a healthy lifespan. We chose to perform a systematic literature review (SLR) as a tool to collect key mtDNA SNPs associated with an increase in lifespan. Then validated our results by comparing them to the MitoMap database. Next, we assessed the effect of relevant SNPs on protein stability. A total of 28 SNPs were found in protein coding regions. These SNPs were reported in Japan, China, Turkey, and India. Among the studied SNPs, the C5178A mutation in the ND2 gene of Complex I of the RC was detected in all the reviewed reports except in Uygur Chinese centenarians. Then, we found that G9055A (ATP6 gene) and A10398G (ND3 gene) polymorphisms have been associated with a protective effect against Parkinson's disease (PD). Additionally, C8414T in ATP8 was significantly associated with longevity in three Japanese reports. Interestingly, using MitoMap we found that G9055A (ATP6 gene) was the only SNP promoting longevity not associated with any pathology. The identification of SNPs associated with an increase in lifespan opens the possibility to better understand individual differences regarding a decrease in illness susceptibility and find strategies that contribute to healthy aging.
    Keywords:  Mitochondria; SNP; aging; longevity; mitochondrial DNA; mitochondrial protein
    DOI:  https://doi.org/10.1016/j.mito.2022.06.008
  11. Cell Biol Int. 2022 Jul 12.
    Tamoxifen modulates mitochondrial dynamics through AMPK and MAPK during nutrition deprivation.
    Gangipangi Vijayakumar, Uppalapati S Swetha, Selvaraju Sudhagar.
      The interaction of cancer cells with their tumor microenvironment determines key events in the progression of the disease, therapeutic efficacy, and the development of drug resistance. Here, we presented evidence that tamoxifen support breast cancer growth during nutrition deprivation by modulating mitochondrial dynamics through AMPK and MAPK signaling. Tamoxifen enhances mitochondrial fusion under nutrition-deprived conditions by suppressing Drp1 ser616 phosphorylation and upregulating Mfn1 levels. Tamoxifen-induced mitochondrial fusion is mediated by the activation of AMPK as evident by the pharmacological inhibition of AMPK reverse mitochondrial fusion. Interestingly, JNK activation by tamoxifen controls the mitochondrial fusion morphology by downregulating Mfn2. Collectively, tamoxifen support cell growth by enhancing mitochondrial fusion by regulating stress kinase signaling under nutrition deprivation condition.
    Keywords:  AMPK; MAPK; Tamoxifen; mitochondrial dynamics; nutrition deprivation
    DOI:  https://doi.org/10.1002/cbin.11853
  12. Commun Biol. 2022 Jul 14. 5(1): 698
    Mitochondrial prohibitin complex regulates fungal virulence via ATG24-assisted mitophagy.
    Yaqin Yan, Jintian Tang, Qinfeng Yuan, Caiyun Liu, Xiaolin Chen, Hao Liu, Junbin Huang, Chonglai Bao, Tom Hsiang, Lu Zheng.
      Prohibitins are highly conserved eukaryotic proteins in mitochondria that function in various cellular processes. The roles of prohibitins in fungal virulence and their regulatory mechanisms are still unknown. Here, we identified the prohibitins ChPhb1 and ChPhb2 in a plant pathogenic fungus Colletotrichum higginsianum and investigated their roles in the virulence of this anthracnose fungus attacking crucifers. We demonstrate that ChPhb1 and ChPhb2 are required for the proper functioning of mitochondria, mitophagy and virulence. ChPhb1 and ChPhb2 interact with the autophagy-related protein ChATG24 in mitochondria, and ChATG24 shares similar functions with these proteins in mitophagy and virulence, suggesting that ChATG24 is involved in prohibitin-dependent mitophagy. ChPhb1 and ChPhb2 modulate the translocation of ChATG24 into mitochondria during mitophagy. The role of ChATG24 in mitophagy is further confirmed to be conserved in plant pathogenic fungi. Our study presents that prohibitins regulate fungal virulence by mediating ATG24-assisted mitophagy.
    DOI:  https://doi.org/10.1038/s42003-022-03666-5
  13. Front Aging. 2021 ;2 681428
    Altered Nutrient Uptake Causes Mitochondrial Dysfunction in Senescent CD8+ EMRA T Cells During Type 2 Diabetes.
    Lauren A Callender, Elizabeth C Carroll, Conor Garrod-Ketchley, Johannes Schroth, Jonas Bystrom, Victoria Berryman, Melanie Pattrick, Desiree Campbell-Richards, Gillian A Hood, Graham A Hitman, Sarah Finer, Sian M Henson.
      Mitochondrial health and cellular metabolism can heavily influence the onset of senescence in T cells. CD8+ EMRA T cells exhibit mitochondrial dysfunction and alterations to oxidative phosphorylation, however, the metabolic properties of senescent CD8+ T cells from people living with type 2 diabetes (T2D) are not known. We show here that mitochondria from T2D CD8+ T cells had a higher oxidative capacity together with increased levels of mitochondrial reactive oxgen species (mtROS), compared to age-matched control cells. While fatty acid uptake was increased, fatty acid oxidation was impaired in T2D CD8+ EMRA T cells, which also showed an accumulation of lipid droplets and decreased AMPK activity. Increasing glucose and fatty acids in healthy CD8+ T cells resulted in increased p-p53 expression and a fragmented mitochondrial morphology, similar to that observed in T2D CD8+ EMRA T cells. The resulting mitochondrial changes are likely to have a profound effect on T cell function. Consequently, a better understanding of these metabolic abnormalities is crucial as metabolic manipulation of these cells may restore correct T cell function and help reduce the impact of T cell dysfunction in T2D.
    Keywords:  T cell; ageing; inflammation; metabolism; mitochondria; senescence; type 2 diabetes
    DOI:  https://doi.org/10.3389/fragi.2021.681428
  14. Inflamm Res. 2022 Jul 11.
    Heme oxygenase-1 protects against endotoxin-induced acute lung injury depends on NAD+-mediated mitonuclear communication through PGC1α/PPARγ signaling pathway.
    Simeng He, Jia Shi, Wenming Liu, Shihan Du, Yuan Zhang, Lirong Gong, Shuan Dong, Xiangyun Li, Qiaoying Gao, Jing Yang, Jianbo Yu.
      Endotoxin-induced acute lung injury (ALI) is a challenging life-threatening disease for which no specific therapy exists. Mitochondrial dysfunction is corroborated as hallmarks in sepsis which commonly disrupt mitochondria-centered cellular communication networks, especially mitonuclear crosstalk, where the ubiquitous cofactor nicotinamide adenine dinucleotide (NAD+) is essential for mitonuclear communication. Heme oxygenase-1 (HO-1) is critical for maintaining mitochondrial dynamic equilibrium and regulating endoplasmic reticulum (ER) and Golgi stress to alleviating acute lung injury. However, it is unclear whether HO-1 regulates NAD+-mediated mitonuclear communication to exert the endogenous protection during endotoxin-induced ALI. In this study, we observed HO-1 attenuated endotoxin-induced ALI by regulated NAD+ levels and NAD+ affected the mitonuclear communication, including mitonuclear protein imbalance and UPRmt to alleviate lung damage. We also found the protective effect of HO-1 depended on NAD+ and NAD+-mediated mitonuclear communication. Furtherly, the inhibition of the PGC1α/PPARγ signaling exacerbates the septic lung injury by reducing NAD+ levels and repressing the mitonuclear protein imbalance and UPRmt. Altogether, our study certified that HO-1 ameliorated endotoxin-induced acute lung injury by regulating NAD+ and NAD+-mediated mitonuclear communications through PGC1α/PPARγ pathway. The present study provided complementary evidence for the cytoprotective effect of HO-1 as a potential target for preventing and attenuating of endotoxin-induced ALI.
    Keywords:  Acute lung injury; Heme oxygenase-1; Mitonuclear communication; NAD+; Sepsis
    DOI:  https://doi.org/10.1007/s00011-022-01605-y
  15. Chin Med J (Engl). 2022 Jul 14.
    CHCHD2 maintains mitochondrial contact site and cristae organizing system stability and protects against mitochondrial dysfunction in an experimental model of Parkinson's disease.
    Lin Lu, Hengxu Mao, Miaomiao Zhou, Yuwan Lin, Wei Dai, Jiewen Qiu, Yousheng Xiao, Mingshu Mo, Xiaoqin Zhu, Zhuohua Wu, Zhong Pei, Wenyuan Guo, Pingyi Xu, Xiang Chen.
      BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's dementia. Mitochondrial dysfunction is involved in the pathology of PD. Coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) was identified as associated with autosomal dominant PD. However, the mechanism of CHCHD2 in PD remains unclear.METHODS: Short hairpin RNA (ShRNA)-mediated CHCHD2 knockdown or lentivirus-mediated CHCHD2 overexpression was performed to investigate the impact of CHCHD2 on mitochondrial morphology and function in neuronal tumor cell lines represented with human neuroblastoma (SHSY5Y) and HeLa cells. Blue-native polyacrylamide gel electrophoresis (PAGE) and two-dimensional sodium dodecyl sulfate-PAGE analysis were used to illustrate the role of CHCHD2 in mitochondrial contact site and cristae organizing system (MICOS). Co-immunoprecipitation and immunoblotting were used to address the interaction between CHCHD2 and Mic10. Serotype injection of adeno-associated vector-mediated CHCHD2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration were used to examine the influence of CHCHD2 in vivo.
    RESULTS: We found that the overexpression of CHCHD2 can protect against methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction and inhibit the loss of dopaminergic neurons in the MPTP-induced mouse model. Furthermore, we identified that CHCHD2 interacted with Mic10, and overexpression of CHCHD2 can protect against MPP+-induced MICOS impairment, while knockdown of CHCHD2 impaired the stability of MICOS.
    CONCLUSION: This study indicated that CHCHD2 could interact with Mic10 and maintain the stability of the MICOS complex, which contributes to protecting mitochondrial function in PD.
    DOI:  https://doi.org/10.1097/CM9.0000000000002053
  16. Biochem J. 2022 Jul 15. 479(13): 1455-1466
    The mitochondrial translocator protein (TSPO): a key multifunctional molecule in the nervous system.
    Léa El Chemali, Yvette Akwa, Liliane Massaad-Massade.
      Translocator protein (TSPO, 18 kDa), formerly known as peripheral benzodiazepine receptor, is an evolutionary well-conserved protein located on the outer mitochondrial membrane. TSPO is involved in a variety of fundamental physiological functions and cellular processes. Its expression levels are regulated under many pathological conditions, therefore, TSPO has been proposed as a tool for diagnostic imaging and an attractive therapeutic drug target in the nervous system. Several synthetic TSPO ligands have thus been explored as agonists and antagonists for innovative treatments as neuroprotective and regenerative agents. In this review, we provide state-of-the-art knowledge of TSPO functions in the brain and peripheral nervous system. Particular emphasis is placed on its contribution to important physiological functions such as mitochondrial homeostasis, energy metabolism and steroidogenesis. We also report how it is involved in neuroinflammation, brain injury and diseases of the nervous system.
    Keywords:  biomarker; neuroinflammation; neuropathology; neuroprotection; steroidogenesis; translocator protein (TSPO)
    DOI:  https://doi.org/10.1042/BCJ20220050
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