bims-mitlys Biomed News
on Mitochondria and Lysosomes
Issue of 2021–08–08
seventeen papers selected by
Nicoletta Plotegher, University of Padova
  1. Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation.
  2. Molecular functions of autophagy adaptors upon ubiquitin-driven mitophagy.
  3. Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice.
  4. Mitophagy: At the heart of mitochondrial quality control in cardiac aging and frailty.
  5. The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder.
  6. Mitochondrion: a sensitive target for Pb exposure.
  7. The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy.
  8. BNIP3-Dependent Mitophagy via PGC1α Promotes Cartilage Degradation.
  9. Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging.
  10. Tomatidine provides mitophagy-independent neuroprotection after ischemic injury.
  11. A fluorescence imaging based-assay to monitor mitophagy in cultured hepatocytes and mouse liver.
  12. Failure to Guard: Mitochondrial Protein Quality Control in Cancer.
  13. Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation.
  14. Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain.
  15. Mammalian Target of Rapamycin Signaling Pathway Regulates Mitochondrial Quality Control of Brown Adipocytes in Mice.
  16. Rapamycin Plus Doxycycline Combination Affects Growth Arrest and Selective Autophagy-Dependent Cell Death in Breast Cancer Cells.
  17. Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3.
  1. Sci Adv. 2021 Aug;pii: eabf6580. [Epub ahead of print]7(32):
    Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation.
    Huihui Li, Zak Doric, Amandine Berthet, Danielle M Jorgens, Mai K Nguyen, Ivy Hsieh, Julia Margulis, Rebecca Fang, Jayanta Debnath, Hiromi Sesaki, Steve Finkbeiner, Eric Huang, Ken Nakamura.
      Altered mitochondrial quality control and dynamics may contribute to neurodegenerative diseases, including Parkinson's disease, but we understand little about these processes in neurons. We combined time-lapse microscopy and correlative light and electron microscopy to track individual mitochondria in neurons lacking the fission-promoting protein dynamin-related protein 1 (Drp1) and delineate the kinetics of PINK1-dependent pathways of mitochondrial quality control. Depolarized mitochondria recruit Parkin to the outer mitochondrial membrane, triggering autophagosome formation, rapid lysosomal fusion, and Parkin redistribution. Unexpectedly, these mitolysosomes are dynamic and persist for hours. Some are engulfed by healthy mitochondria, and others are deacidified before bursting. In other cases, Parkin is directly recruited to the matrix of polarized mitochondria. Loss of PINK1 blocks Parkin recruitment, causes LC3 accumulation within mitochondria, and exacerbates Drp1KO toxicity to dopamine neurons. These results define a distinct neuronal mitochondrial life cycle, revealing potential mechanisms of mitochondrial recycling and signaling relevant to neurodegeneration.
    DOI:  https://doi.org/10.1126/sciadv.abf6580
  2. Biochim Biophys Acta Gen Subj. 2021 Jul 28. pii: S0304-4165(21)00131-8. [Epub ahead of print]1865(10): 129972
    Molecular functions of autophagy adaptors upon ubiquitin-driven mitophagy.
    Koji Yamano, Waka Kojima.
       BACKGROUND: Perturbations in organellar health can lead to an accumulation of unwanted and/or damaged organelles that are toxic to the cell and which can contribute to the onset of neurodegenerative diseases such as Parkinson's disease. Mitochondrial health is particularly critical given the indispensable role the organelle has not only in adenosine triphosphate production but also other metabolic processes. Byproducts of oxidative respiration, such as reactive oxygen species, however, can negatively impact mitochondrial fitness. Consequently, selective degradation of damaged mitochondria, which occurs via a specific autophagic process termed mitophagy, is essential for normal cell maintenance.
    SCOPE OF REVIEW: Recent accumulating evidence has shown that autophagy adaptors (also referred to as autophagy receptors) play critical roles in connecting ubiquitinated mitochondria with the autophagic machinery of the autophagy-lysosome pathway that is required for degradation. In this review, we focus on our current understanding of the autophagy adaptor mechanisms underlying PINK1/Parkin-driven mitophagy.
    MAJOR CONCLUSIONS: Although autophagy adaptors are canonically defined as proteins that possess ubiquitin-binding domains and ATG8s-binding motifs, the recent identification of novel binding partners has contributed to the development of a more sophisticated model for how autophagy adaptors contribute to the molecular hub that organizes autophagic cargo-degradation.
    GENERAL SIGNIFICANCE: Although mitophagy is recognized as one of the selective autophagy pathways that removes dysfunctional mitochondria, a more nuanced understanding of the interactions connecting autophagy adaptors and their associated proteins is needed to gain deeper insights into the fundamental biological processes underlying human diseases, including neurodegenerative disorders. This review is part of a Special Issue entitled Mitophagy.
    DOI:  https://doi.org/10.1016/j.bbagen.2021.129972
  3. Elife. 2021 Aug 03. pii: e67604. [Epub ahead of print]10
    Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice.
    Francois Singh, Alan R Prescott, Philippa Rosewell, Graeme Ball, Alastair D Reith, Ian G Ganley.
      Parkinson's disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation - key features of the autophagy of mitochondria, known as mitophagy. Here, we investigated the role of LRRK2, a protein kinase frequently mutated in PD, in this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson's disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.
    Keywords:  LRRK2; Mitophagy; cell biology; kinase inhibitor; mito-QC; mouse; neuroscience; parkinson's disease
    DOI:  https://doi.org/10.7554/eLife.67604
  4. Exp Gerontol. 2021 Aug 03. pii: S0531-5565(21)00290-4. [Epub ahead of print] 111508
    Mitophagy: At the heart of mitochondrial quality control in cardiac aging and frailty.
    Anna Picca, Riccardo Calvani, Hélio José Coelho-Júnior, Emanuele Marzetti.
      Cardiovascular disease is highly prevalent among older adults and poses a huge burden on morbidity, disability, and mortality. The age-related increased vulnerability of the cardiovascular system towards stressors is as a pathophysiological trait of cardiovascular disease. This has been associated with a progressive deterioration of blood vessels and decline in heart function during aging. Cardiomyocytes rely mostly on oxidative metabolism for deploying their activities and mitochondrial metabolism is crucial to this purpose. Dysmorphic, inefficient, and oxidant-producing mitochondria have been identified in aged cardiomyocytes in the setting of cardiac structural and functional alterations. These aberrant organelles are thought to arise from inefficient mitochondrial quality control, which has therefore been place in the spotlight as a relevant mechanism of cardiac aging. As a result of alterations in mitochondrial quality control and imbalanced oxidant defense, mitochondrial damage accumulates and contributes to cardiac frailty. Herein, we discuss the contribution of defective mitochondrial quality control pathways to cardiac frailty. Emerging findings pointing towards the exploitation of these pathways as therapeutic targets against cardiac aging and cardiovascular disease will also be illustrated.
    Keywords:  Autophagy; Cardioprotection; Extracellular vesicles; Mitochondrial derived vesicles; Mitochondrial quality control; Therapeutics
    DOI:  https://doi.org/10.1016/j.exger.2021.111508
  5. EMBO Rep. 2021 Aug 05. e51991
    The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder.
    Esther Nuebel, Jeffrey T Morgan, Sarah Fogarty, Jacob M Winter, Sandra Lettlova, Jordan A Berg, Yu-Chan Chen, Chelsea U Kidwell, J Alan Maschek, Katie J Clowers, Catherine Argyriou, Lingxiao Chen, Ilka Wittig, James E Cox, Minna Roh-Johnson, Nancy Braverman, Joshua Bonkowsky, Steven P Gygi, Jared Rutter.
      Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs-Zellweger spectrum disorder (ZSD)-is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter-organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.
    Keywords:  mitochondria; mitochondrial quality control; peroxisomal biogenesis disorder; peroxisomal import; peroxisomes
    DOI:  https://doi.org/10.15252/embr.202051991
  6. J Toxicol Sci. 2021 ;46(8): 345-358
    Mitochondrion: a sensitive target for Pb exposure.
    Qing Han, Wei Zhang, JingChong Guo, Qian Zhu, Hui Chen, YongLi Xia, Gaochun Zhu.
      Pb exposure is a worldwide environmental contamination issue which has been of concern to more and more people. Exposure to environmental Pb and its compounds through food and respiratory routes causes toxic damage to the digestive, respiratory, cardiovascular and nervous systems, etc. Children and pregnant women are particularly vulnerable to Pb. Pb exposure significantly destroys children's learning ability, intelligence and perception ability. Mitochondria are involved in various life processes of eukaryotes and are one of the most sensitive organelles to various injuries. There is no doubt that Pb-induced mitochondrial damage can widely affect various physiological processes and cause great harm. In this review, we summarized the toxic effects of Pb on mitochondria which led to various pathological processes. Pb induces mitochondrial dysfunction leading to the increased level of oxidative stress. In addition, Pb leads to cell apoptosis via mitochondrial permeability transition pore (MPTP) opening. Also, Pb can stimulate the development of mitochondria-mediated inflammatory responses. Furthermore, Pb triggers the germination of autophagy via the mitochondrial pathway and induces mitochondrial dysfunction, disturbing intracellular calcium homeostasis. In a word, we discussed the effects of Pb exposure on mitochondria, hoping to provide some references for further research and better therapeutic options for Pb exposure.
    Keywords:  Autophagy; Calcium homeostasis; Inflammation; Mitochondrial permeability transition pore; Oxidative stress; ​Pb exposure
    DOI:  https://doi.org/10.2131/jts.46.345
  7. Life (Basel). 2021 Jul 04. pii: 648. [Epub ahead of print]11(7):
    The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy.
    Andrea L Reid, Matthew S Alexander.
      Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack of dystrophin in the muscle results in myofiber death, fibrotic infiltration, and mitochondrial dysfunction. There is no cure for DMD, although dystrophin-replacement gene therapies and exon-skipping approaches are being pursued in clinical trials. Mitochondrial dysfunction is one of the first cellular changes seen in DMD myofibers, occurring prior to muscle disease onset and progresses with disease severity. This is seen by reduced mitochondrial function, abnormal mitochondrial morphology and impaired mitophagy (degradation of damaged mitochondria). Dysfunctional mitochondria release high levels of reactive oxygen species (ROS), which can activate pro-inflammatory pathways such as IL-1β and IL-6. Impaired mitophagy in DMD results in increased inflammation and further aggravates disease pathology, evidenced by increased muscle damage and increased fibrosis. This review will focus on the critical interplay between mitophagy and inflammation in Duchenne muscular dystrophy as a pathological mechanism, as well as describe both candidate and established therapeutic targets that regulate these pathways.
    Keywords:  DMD; dystrophin; dystrophy; inflammation; mitophagy
    DOI:  https://doi.org/10.3390/life11070648
  8. Cells. 2021 Jul 20. pii: 1839. [Epub ahead of print]10(7):
    BNIP3-Dependent Mitophagy via PGC1α Promotes Cartilage Degradation.
    Deokha Kim, Jinsoo Song, Eun-Jung Jin.
      Since mitochondria are suggested to be important regulators in maintaining cartilage homeostasis, turnover of mitochondria through mitochondrial biogenesis and mitochondrial degradation may play an important role in the pathogenesis of osteoarthritis (OA). Here, we found that mitochondrial dysfunction is closely associated with OA pathogenesis and identified the peroxisome proliferator-activated receptor-gamma co-activator 1-alpha (PGC1α) as a potent regulator. The expression level of PGC1α was significantly decreased under OA conditions, and knockdown of PGC1α dramatically elevated the cartilage degradation by upregulating cartilage degrading enzymes and apoptotic cell death. Interestingly, the knockdown of PGC1α activated the parkin RBR E3 ubiquitin protein ligase (PRKN)-independent selective mitochondria autophagy (mitophagy) pathway through the upregulation of BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3). The overexpression of BNIP3 stimulated mitophagy and cartilage degradation by upregulating cartilage-degrading enzymes and chondrocyte death. We identified microRNA (miR)-126-5p as an upstream regulator for PGC1α and confirmed the direct binding between miR-126-5p and 3' untranslated region (UTR) of PGC1α. An in vivo OA mouse model induced by the destabilization of medial meniscus (DMM) surgery, and the delivery of antago-miR-126 via intra-articular injection significantly decreased cartilage degradation. In sum, the loss of PGC1α in chondrocytes due to upregulation of miR-126-5p during OA pathogenesis resulted in the activation of PRKN-independent mitophagy through the upregulation of BNIP3 and stimulated cartilage degradation and apoptotic death of chondrocytes. Therefore, the regulation of PGC1α:BNIP3 mitophagy axis could be of therapeutic benefit to cartilage-degrading diseases.
    Keywords:  BNIP3; PGC1A; autophagy; miR-126-5p; mitophagy; osteoarthritis
    DOI:  https://doi.org/10.3390/cells10071839
  9. Int J Mol Sci. 2021 Jul 30. pii: 8179. [Epub ahead of print]22(15):
    Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging.
    Jean-Philippe Leduc-Gaudet, Sabah N A Hussain, Esther Barreiro, Gilles Gouspillou.
      The maintenance of mitochondrial integrity is critical for muscle health. Mitochondria, indeed, play vital roles in a wide range of cellular processes, including energy supply, Ca2+ homeostasis, retrograde signaling, cell death, and many others. All mitochondria-containing cells, including skeletal muscle cells, dispose of several pathways to maintain mitochondrial health, including mitochondrial biogenesis, mitochondrial-derived vesicles, mitochondrial dynamics (fusion and fission process shaping mitochondrial morphology), and mitophagy-the process in charge of the removal of mitochondria though autophagy. The loss of skeletal muscle mass (atrophy) is a major health problem worldwide, especially in older people. Currently, there is no treatment to counteract the progressive decline in skeletal muscle mass and strength that occurs with aging, a process termed sarcopenia. There is increasing data, including our own, suggesting that accumulation of dysfunctional mitochondria contributes to the development of sarcopenia. Impairments in mitochondrial dynamics and mitophagy were recently proposed to contribute to sarcopenia. This review summarizes the current state of knowledge on the role played by mitochondrial dynamics and mitophagy in skeletal muscle health and in the development of sarcopenia. We also highlight recent studies showing that enhancing mitophagy in skeletal muscle is a promising therapeutic target to prevent or even treat skeletal muscle dysfunction in the elderly.
    Keywords:  aging; autophagy; mitochondrial dynamics; mitophagy; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms22158179
  10. FEBS Open Bio. 2021 Aug 04.
    Tomatidine provides mitophagy-independent neuroprotection after ischemic injury.
    Yu-Ting Wang, Li-Na Zhang, Xiao-Cui Lyu, Yue Li, Anil Ahsan, Zikai Feng, Xiangnan Zhang.
      Cerebral ischemia is one of the leading causes of human mortality and disability worldwide. The treatment of cerebral ischemia is refractory due to its short therapeutic window and lack of effective clinical drugs. Mitophagy, the autophagic elimination of damaged mitochondria, attenuates neuronal injury in cerebral ischemia, indicating the potential of mitophagy inducers as therapies for cerebral ischemia. We previously determined that, by enhancing autophagy flux, the steroidal alkaloid tomatidine can function as a neuroprotective agent against ischemic injury. However, its effects on mitophagy remain unknown. For this purpose, neuroblastoma cell lines Neuro-2a (N2a) and SH-SY5Y were subjected to ischemic injury induced by oxygen-glucose deprivation/reperfusion (OGD/R), then treated with tomatidine. OGD/R induced a general decrease of cellular contents, and the present study revealed that tomatidine had no impact on mitophagy. In addition, tomatidine did not affect mitochondrial contents, including translocase of outer mitochondrial membrane 20 (TOM20) and voltage-dependent anion channel 1 (VDAC1), in either OGD/R-treated or intact SH-SY5H cells. Our results indicate that tomatidine exhibits its neuroprotective effects by enhancing autophagy but potentially mitophagy-independent manner, and provide insights for further investigation into its mechanism(s) and potential therapeutic use against cerebral ischemia.
    Keywords:  autophagy; cerebral ischemia; mitophagy; tomatidine
    DOI:  https://doi.org/10.1002/2211-5463.13265
  11. Liver Res. 2021 Mar;5(1): 16-20
    A fluorescence imaging based-assay to monitor mitophagy in cultured hepatocytes and mouse liver.
    Xiaowen Ma, Wen-Xing Ding.
       Background and aim: Mitophagy is a lysosomal degradation pathway that selectively removes damaged, aged and dysfunctional mitochondria. Recent advances in understanding mitophagy highlight its importance in various physiological and pathological conditions including liver diseases. However, reliable quantitative assays to monitor mitophagy in cultured cells and in tissues are still scarce.
    Methods: We describe a detailed protocol for monitoring mitophagy in primary cultured hepatocytes and mouse livers using cytochrome C oxidase subunit 8 (Cox8)-enhanced green fluorescent protein (EGFP)-mCherry, a dual color fluorescence based-imaging method.
    Results: Mitochondria are visualized in yellow fluorescence due to the merged EGFP and mCherry signal. In contrast, autolysosome enclosed mitochondria are shown as red puncta due to quenching of EGFP green fluorescence in acidic compartments. Quantifying the number of red-only puncta in each cell can obtain a quantitative measure for mitophagy.
    Conclusions: Cox8-EGFP-mCherry assay can specifically target to mitochondria and be used to monitor mitophagy in vitro and in vivo.
    Keywords:  Autophagy; Cox8-EGFP-mCherry; Fluorescence microscopy; Lysosome; Mitochondria
    DOI:  https://doi.org/10.1016/j.livres.2020.12.002
  12. Int J Mol Sci. 2021 Aug 02. pii: 8306. [Epub ahead of print]22(15):
    Failure to Guard: Mitochondrial Protein Quality Control in Cancer.
    Joseph E Friedlander, Ning Shen, Aozhuo Zeng, Sovannarith Korm, Hui Feng.
      Mitochondria are energetic and dynamic organelles with a crucial role in bioenergetics, metabolism, and signaling. Mitochondrial proteins, encoded by both nuclear and mitochondrial DNA, must be properly regulated to ensure proteostasis. Mitochondrial protein quality control (MPQC) serves as a critical surveillance system, employing different pathways and regulators as cellular guardians to ensure mitochondrial protein quality and quantity. In this review, we describe key pathways and players in MPQC, such as mitochondrial protein translocation-associated degradation, mitochondrial stress responses, chaperones, and proteases, and how they work together to safeguard mitochondrial health and integrity. Deregulated MPQC leads to proteotoxicity and dysfunctional mitochondria, which contributes to numerous human diseases, including cancer. We discuss how alterations in MPQC components are linked to tumorigenesis, whether they act as drivers, suppressors, or both. Finally, we summarize recent advances that seek to target these alterations for the development of anti-cancer drugs.
    Keywords:  MPQC; cancer; chaperone; mitochondria; oncogene; protease; proteostasis; therapeutic targeting; tumor suppressor; tumorigenesis
    DOI:  https://doi.org/10.3390/ijms22158306
  13. Development. 2021 Aug 06. pii: dev.199686. [Epub ahead of print]
    Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation.
    Grigor Varuzhanyan, Mark S Ladinsky, Shun-Ichi Yamashita, Manabu Abe, Kenji Sakimura, Tomotake Kanki, David C Chan.
      Male germline development involves choreographed changes to mitochondrial number, morphology, and organization. Mitochondrial reorganization during spermatogenesis was recently shown to require mitochondrial fusion and fission. Mitophagy, the autophagic degradation of mitochondria, is another mechanism for controlling mitochondrial number and physiology, but its role during spermatogenesis is largely unknown. During post-meiotic spermatid development, restructuring of the mitochondrial network results in packing of mitochondria into a tight array in the sperm midpiece to fuel motility. Here, we show that disruption of mouse Fis1 in the male germline results in early spermatid arrest that is associated with increased mitochondrial content. Mutant spermatids coalesce into multinucleated giant cells (GCs) that accumulate mitochondria of aberrant ultrastructure and numerous mitophagic and autophagic intermediates, suggesting a defect in mitophagy. We conclude that Fis1 regulates mitochondrial morphology and turnover to promote spermatid maturation.
    Keywords:  Autophagy; Mitochondrial dynamics; Mitophagy; Spermatid; Spermatogenesis
    DOI:  https://doi.org/10.1242/dev.199686
  14. Int J Mol Sci. 2021 Jul 31. pii: 8275. [Epub ahead of print]22(15):
    Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain.
    Pavel A Melentev, Elena V Ryabova, Nina V Surina, Darya R Zhmujdina, Artem E Komissarov, Ekaterina A Ivanova, Natalia P Boltneva, Galina F Makhaeva, Mariana I Sliusarenko, Andriy S Yatsenko, Iryna I Mohylyak, Nataliya P Matiytsiv, Halyna R Shcherbata, Svetlana V Sarantseva.
      Various neurodegenerative disorders are associated with human NTE/PNPLA6 dysfunction. Mechanisms of neuropathogenesis in these diseases are far from clearly elucidated. Hereditary spastic paraplegia belongs to a type of neurodegeneration associated with NTE/PNLPLA6 and is implicated in neuron death. In this study, we used Drosophila melanogaster to investigate the consequences of neuronal knockdown of swiss cheese (sws)-the evolutionarily conserved ortholog of human NTE/PNPLA6-in vivo. Adult flies with the knockdown show longevity decline, locomotor and memory deficits, severe neurodegeneration progression in the brain, reactive oxygen species level acceleration, mitochondria abnormalities and lipid droplet accumulation. Our results suggest that SWS/NTE/PNPLA6 dysfunction in neurons induces oxidative stress and lipid metabolism alterations, involving mitochondria dynamics and lipid droplet turnover in neurodegeneration pathogenesis. We propose that there is a complex mechanism in neurological diseases such as hereditary spastic paraplegia, which includes a stress reaction, engaging mitochondria, lipid droplets and endoplasmic reticulum interplay.
    Keywords:  Drosophila melanogaster; NTE; PNPLA6; ROS; hereditary spastic paraplegia; lipid droplets; mitochondria; neurodegeneration; oxidative stress; swiss cheese
    DOI:  https://doi.org/10.3390/ijms22158275
  15. Front Physiol. 2021 ;12 638352
    Mammalian Target of Rapamycin Signaling Pathway Regulates Mitochondrial Quality Control of Brown Adipocytes in Mice.
    Bahetiyaer Huwatibieke, Wenzhen Yin, Lingchao Liu, Yuxin Jin, Xinxin Xiang, Jingyan Han, Weizhen Zhang, Yin Li.
      The mammalian target of rapamycin (mTOR) is an important protein kinase that senses changes in extracellular and intracellular energy levels and plays a key role in regulating energy metabolism. Brown adipose tissue, which can be converted to white adipose tissue, contains a large number of mitochondria and regulates energy expenditure through thermogenesis. Because obesity is a process of fat accumulation due to chronic excessive energy intake, we attempted to determine whether the mTOR signaling pathway can affect the mitochondrial quality control of brown adipocytes through sensing energy status, thereby regulating brown/white adipocyte transformation. In the present study, through activation or inhibition of mTOR signaling, we detected mitochondrial biogenesis, dynamics, and autophagy-related markers in brown adipocytes. We found that activation of mTOR signaling downregulated the expression of mitochondrial biogenesis, dynamics, and autophagy-relevant markers and inhibited the mitochondrial quality control of brown adipocytes, indicating a phenotypic transformation of brown to white adipocytes. In contrast, inhibition of mTOR signaling upregulated the expression of mitochondrial biogenesis, dynamics, and mitophagy-relevant markers and strengthened mitochondrial quality control, suggesting an inhibition of the phenotypic transformation of brown to white adipocytes. In conclusion, the mTOR signaling pathway plays an important role in modulating the transformation of adipocytes by regulating mitochondrial quality control.
    Keywords:  brown adipose tissue; mammalian target of rapamycin; mitochondria; obesity; white adipose tissue
    DOI:  https://doi.org/10.3389/fphys.2021.638352
  16. Int J Mol Sci. 2021 Jul 27. pii: 8019. [Epub ahead of print]22(15):
    Rapamycin Plus Doxycycline Combination Affects Growth Arrest and Selective Autophagy-Dependent Cell Death in Breast Cancer Cells.
    Titanilla Dankó, Gábor Petővári, Dániel Sztankovics, Dorottya Moldvai, Regina Raffay, Péter Lőrincz, Tamás Visnovitz, Viktória Zsiros, Gábor Barna, Ágnes Márk, Ildikó Krencz, Anna Sebestyén.
      Metabolic alteration is characteristic during tumour growth and therapy; however, targeting metabolic rewiring could overcome therapy resistance. mTOR hyperactivity, autophagy and other metabolic processes, including mitochondrial functions, could be targeted in breast cancer progression. We investigated the growth inhibitory mechanism of rapamycin + doxycycline treatment in human breast cancer model systems. Cell cycle and cell viability, including apoptotic and necrotic cell death, were analysed using flow cytometry, caspase activity measurements and caspase-3 immunostainings. mTOR-, autophagy-, necroptosis-related proteins and treatment-induced morphological alterations were analysed by WesTM, Western blot, immunostainings and transmission electron microscopy. The rapamycin + doxycycline combination decreased tumour proliferation in about 2/3rd of the investigated cell lines. The continuous treatment reduced tumour growth significantly both in vivo and in vitro. The effect after short-term treatment was reversible; however, autophagic vacuoles and degrading mitochondria were detected simultaneously, and the presence of mitophagy was also observed after the long-term rapamycin + doxycycline combination treatment. The rapamycin + doxycycline combination did not cause apoptosis or necrosis/necroptosis, but the alterations in autophagy- and mitochondria-related protein levels (LC3-B-II/I, p62, MitoTracker, TOM20 and certain co-stainings) were correlated to autophagy induction and mitophagy, without mitochondria repopulation. Based on these results, we suggest considering inducing metabolic stress and targeting mTOR hyperactivity and mitochondrial functions in combined anti-cancer treatments.
    Keywords:  autophagy; cell death; doxycycline; mitophagy; rapamycin; tumour growth
    DOI:  https://doi.org/10.3390/ijms22158019
  17. Int J Mol Sci. 2021 Jul 29. pii: 8117. [Epub ahead of print]22(15):
    Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3.
    Nunzia D'Onofrio, Elisa Martino, Luigi Mele, Antonino Colloca, Martina Maione, Domenico Cautela, Domenico Castaldo, Maria Luisa Balestrieri.
      Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.
    Keywords:  PINK1/Parkin; colon cancer; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3390/ijms22158117
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