bims-mitlys Biomed News
on Mitochondria and Lysosomes
Issue of 2021‒06‒06
ten papers selected by
Nicoletta Plotegher
University of Padua

  1. Autophagy. 2021 Jun 04.
      Cardiac function is highly reliant on mitochondrial oxidative metabolism and quality control. The circadian Clock gene is critically linked to vital physiological processes including mitochondrial fission, fusion and bioenergetics; however, little is known of how the Clock gene regulates these vital processes in the heart. Herein, we identified a putative circadian CLOCK-mitochondrial interactome that gates an adaptive survival response during myocardial ischemia. We show by transcriptome and gene ontology mapping in CLOCK Δ19/Δ19 mouse that Clock transcriptionally coordinates the efficient removal of damaged mitochondria during myocardial ischemia by directly controlling transcription of genes required for mitochondrial fission, fusion and macroautophagy/autophagy. Loss of Clock gene activity impaired mitochondrial turnover resulting in the accumulation of damaged reactive oxygen species (ROS)-producing mitochondria from impaired mitophagy. This coincided with ultrastructural defects to mitochondria and impaired cardiac function. Interestingly, wild type CLOCK but not mutations of CLOCK defective for E-Box binding or interaction with its cognate partner ARNTL/BMAL-1 suppressed mitochondrial damage and cell death during acute hypoxia. Interestingly, the autophagy defect and accumulation of damaged mitochondria in CLOCK-deficient cardiac myocytes were abrogated by restoring autophagy/mitophagy. Inhibition of autophagy by ATG7 knockdown abrogated the cytoprotective effects of CLOCK. Collectively, our results demonstrate that CLOCK regulates an adaptive stress response critical for cell survival by transcriptionally coordinating mitochondrial quality control mechanisms in cardiac myocytes. Interdictions that restore CLOCK activity may prove beneficial in reducing cardiac injury in individuals with disrupted circadian CLOCK.
    Keywords:  autophagy; clock; metabolism; mitochondrion; myocardial infarction
  2. NPJ Syst Biol Appl. 2021 Jun 02. 7(1): 26
      Spatiotemporal compartmentation of calcium dynamics is critical for neuronal function, particularly in postsynaptic spines. This exquisite level of Ca2+ compartmentalization is achieved through the storage and release of Ca2+ from various intracellular organelles particularly the endoplasmic reticulum (ER) and the mitochondria. Mitochondria and ER are established storage organelles controlling Ca2+ dynamics in neurons. Mitochondria also generate a majority of energy used within postsynaptic spines to support the downstream events associated with neuronal stimulus. Recently, high resolution microscopy has unveiled direct contact sites between the ER and the mitochondria (MERCs), which directly channel Ca2+ release from the ER into the mitochondrial membrane. In this study, we develop a computational 3D reaction-diffusion model to investigate the role of MERCs in regulating Ca2+ and ATP dynamics. This spatiotemporal model accounts for Ca2+ oscillations initiated by glutamate stimulus of metabotropic and ionotropic glutamate receptors and Ca2+ changes in four different compartments: cytosol, ER, mitochondria, and the MERC microdomain. Our simulations predict that the organization of these organelles and inter-organellar contact sites play a key role in modulating Ca2+ and ATP dynamics.We further show that the crosstalk between geometry (mitochondria and MERC) and metabolic parameters (cytosolic ATP hydrolysis, ATP generation) influences the neuronal energy state. Our findings shed light on the importance of organelle interactions in predicting Ca2+ dynamics in synaptic signaling. Overall, our model predicts that a combination of MERC linkage and mitochondria size is necessary for optimal ATP production in the cytosol.
  3. Int J Mol Sci. 2021 May 13. pii: 5179. [Epub ahead of print]22(10):
      Periods of muscle disuse promote marked mitochondrial alterations that contribute to the impaired metabolic health and degree of atrophy in the muscle. Thus, understanding the molecular underpinnings of muscle mitochondrial decline with prolonged inactivity is of considerable interest. There are translational applications to patients subjected to limb immobilization following injury, illness-induced bed rest, neuropathies, and even microgravity. Studies in these patients, as well as on various pre-clinical rodent models have elucidated the pathways involved in mitochondrial quality control, such as mitochondrial biogenesis, mitophagy, fission and fusion, and the corresponding mitochondrial derangements that underlie the muscle atrophy that ensues from inactivity. Defective organelles display altered respiratory function concurrent with increased accumulation of reactive oxygen species, which exacerbate myofiber atrophy via degradative pathways. The preservation of muscle quality and function is critical for maintaining mobility throughout the lifespan, and for the prevention of inactivity-related diseases. Exercise training is effective in preserving muscle mass by promoting favourable mitochondrial adaptations that offset the mitochondrial dysfunction, which contributes to the declines in muscle and whole-body metabolic health. This highlights the need for further investigation of the mechanisms in which mitochondria contribute to disuse-induced atrophy, as well as the specific molecular targets that can be exploited therapeutically.
    Keywords:  apoptosis; autophagy; mitochondrial biogenesis; mitochondrial quality control; mitophagy; muscle disuse; reactive oxygen species; skeletal muscle atrophy
  4. Int J Mol Sci. 2021 May 20. pii: 5379. [Epub ahead of print]22(10):
      Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of the present study consists of detailing an mTOR-dependent mitophagy occlusion, along with suppression of mitochondrial fission. These phenomena contribute to explain the increase in altered mitochondria reported here. Administration of the mTOR inhibitor rapamycin rescues mitochondrial alterations. In detail, rapamycin induces the expression of genes promoting mitophagy (PINK1, PARKIN, ULK1, AMBRA1) and mitochondrial fission (FIS1, DRP1). This occurs along with over-expression of VPS34, an early gene placed upstream in the autophagy pathway. The topographic stoichiometry of proteins coded by these genes within mitochondria indicates that, a remarkable polarization of proteins involved in fission and mitophagy within mitochondria including LC3 takes place. Co-localization of these proteins within mitochondria, persists for weeks following rapamycin, which produces long-lasting mitochondrial plasticity. Thus, rapamycin restores mitochondrial status in GBM cells. These findings add novel evidence about mitochondria and GBM, while fostering a novel therapeutic approach to restore healthy mitochondria through mTOR inhibition.
    Keywords:  AMBRA1; DRP1; FIS1; OPA1; PARKIN; PINK1; ULK1; VPS34; autophagy; mitochondria
  5. Int J Mol Sci. 2021 May 26. pii: 5675. [Epub ahead of print]22(11):
      Oxidative stress occurs in a variety of clinical liver diseases and causes cellular damage and mitochondrial dysfunction. The clearance of damaged mitochondria by mitophagy may facilitate mitochondrial biogenesis and enhance cell survival. Although the supplementation of docosahexaenoic acid (DHA) has been recognized to relieve the symptoms of various liver diseases, the antioxidant effect of DHA in liver disease is still unclear. The purpose of our research was to investigate the antioxidant effect of DHA in the liver and the possible role of mitophagy in this. In vitro, H2O2-induced injury was caused in AML12 cells. The results showed that DHA repressed the level of reactive oxygen species (ROS) induced by H2O2 and stimulated the cellular antioxidation response. Most notably, DHA restored oxidative stress-impaired autophagic flux and promoted protective autophagy. In addition, PINK/Parkin-mediated mitophagy was activated by DHA in AML12 cells and alleviated mitochondrial dysfunction. The ERK1/2 signaling pathway was inhibited during oxidative stress but reactivated by DHA treatment. It was proven that the expression of ERK1/2 was involved in the regulation of mitophagy by the ERK1/2 inhibitor. We further proved these results in vivo. DHA effectively alleviated the liver oxidative damage caused by CCl4 and enhanced antioxidation capacity; intriguingly, autophagy was also activated. In summary, our data demonstrated that DHA protected hepatocytes from oxidative damage through GPR120/ERK-mediated mitophagy.
    Keywords:  DHA; ERK1/2 signaling; liver injury; mitophagy; oxidative stress
  6. Int J Mol Sci. 2021 May 27. pii: 5753. [Epub ahead of print]22(11):
      Mitochondrial function is at the nexus of pathways regulating synaptic-plasticity and cellular resilience. The involvement of brain mitochondrial dysfunction along with increased reactive oxygen species (ROS) levels, accumulating mtDNA mutations, and attenuated autophagy is implicated in psychiatric and neurodegenerative diseases. We have previously modeled mild mitochondrial dysfunction assumed to occur in bipolar disorder (BPD) using exposure of human neuronal cells (SH-SY5Y) to rotenone (an inhibitor of mitochondrial-respiration complex-I) for 72 and 96 h, which exhibited up- and down-regulation of mitochondrial respiration, respectively. In this study, we aimed to find out whether autophagy enhancers (lithium, trehalose, rapamycin, and resveratrol) and/or ROS scavengers [resveratrol, N-acetylcysteine (NAC), and Mn-Tbap) can ameliorate neuronal mild mitochondrial dysfunction. Only lithium (added for the last 24/48 h of the exposure to rotenone for 72/96 h, respectively) counteracted the effect of rotenone on most of the mitochondrial respiration parameters (measured as oxygen consumption rate (OCR)). Rapamycin, resveratrol, NAC, and Mn-Tbap counteracted most of rotenone's effects on OCR parameters after 72 h, possibly via different mechanisms, which are not necessarily related to their ROS scavenging and/or autophagy enhancement effects. The effect of lithium reversing rotenone's effect on OCR parameters is compatible with lithium's known positive effects on mitochondrial function and is possibly mediated via its effect on autophagy. By-and-large it may be summarized that some autophagy enhancers/ROS scavengers alleviate some rotenone-induced mild mitochondrial changes in SH-SY5Y cells.
    Keywords:  ROS scavengers; autophagy enhancers; bipolar disorder; mitochondrial dysfunction; rotenone
  7. Traffic. 2021 Jun 05.
      Mitochondria play important roles in energy generation and homeostasis maintenance in eukaryotic cells. The damaged or superfluous mitochondria can be nonselectively or selectively removed through the autophagy/lysosome pathway, which was referred as mitophagy. According to the molecular machinery for degrading mitochondria, the selectively removed mitochondria can occur through macromitophagy or micromitophagy. In this study, we show that the endosomal sorting complex required for transport III (ESCRT-III) in budding yeast regulates macromitophagy induced by nitrogen starvation, but not by the post-logarithmic phase growth in lactate medium by monitoring a mitochondrial marker, Om45. Firstly, loss of ESCRT-III subunit Snf7 or Vps4-Vta1 complex subunit Vps4, two representative subunits of the ESCRT complex, suppresses the delivery and degradation of Om45-GFP to vacuoles. Secondly, we show that the mitochondrial marker Om45 and mitophagy receptor Atg32 accumulate on autophagosomes marked with Atg8 (mitophagosomes, MPs) in ESCRT mutants. Moreover, the protease-protection assay indicates that Snf7 and Vps4 are involved in MP closure. Finally, Snf7 interacts with Atg11, which was detected by two ways, GST pulldown and BiFC, and this BiFC interaction happens on mitochondrial reticulum. Therefore, we proposed that the ESCRT-III machinery mediates nitrogen starvation-induced macromitophagy by the interaction between Snf7 and Atg11 so that Snf7 is recruited to Atg32 marked MPs by the known Atg11-Atg32 interaction to seal them. These results reveal that the ESCRT-III complex plays a new role in yeast on macromitophagy.
    Keywords:  Atg11; Atg32; ESCRT; Macromitophagy; Micromitophagy; Mitophagosome; Mitophagy, Snf7; Vps4
  8. Endocrinology. 2021 Jun 04. pii: bqab112. [Epub ahead of print]
      Skeletal muscle (SM) weakness occurs in hypothyroidism and resistance to thyroid hormone alpha (RTHα) syndrome. However, the cell signaling and molecular mechanism(s) underlying muscle weakness under these conditions is not well understood. We thus examined the role of thyroid hormone receptor alpha (TRα), the predominant TR isoform in SM, on autophagy, mitochondrial biogenesis and metabolism to demonstrate the molecular mechanism(s) underlying muscle weakness in these two conditions.Two genetic mouse models, TRα1  PV/+ mice which expresses mutant Thra1PV gene ubiquitously, and SM-TRα1  L400R/+ mice, which expresses TRα1  L400R in a muscle-specific manner, were used in this study. Gastrocnemius muscle from TRα1  PV/+, SM-TRα1  L400R/+, and their control mice was harvested for analyses. We demonstrated that loss of TRα1 signaling in gastrocnemius muscle from both the genetic mouse models led to decreased autophagy as evidenced by accumulation of p62 and decreased expression of lysosomal markers (LAMP1, and LAMP2) and lysosomal proteases (cathepsin B and cathepsin D). The expression of PGC1α, TFAM, and ERRα, key factors contributing to mitochondrial biogenesis as well as mitochondrial proteins were decreased, suggesting that there was reduced mitochondrial biogenesis due to the expression of mutant TRα1. Transcriptomic and metabolomic analyses of SM suggested that lipid catabolism was impaired, and was associated with decreased acylcarnitines and tricarboxylic acid cycle (TCA cycle) intermediates in the SM from the mouse line expressing SM-specific mutant TRα1. Our results provide new insight into TRα1-mediated cell signaling, molecular, and metabolic changes that occur in SM when TR action is impaired.
    Keywords:  TRα1 mutation; autophagy; lipid metabolism; mitochondrial function; muscle
  9. Cell Rep. 2021 Jun 01. pii: S2211-1247(21)00552-0. [Epub ahead of print]35(9): 109203
      In multiple species, certain tissue types are prone to acquiring greater loads of mitochondrial genome (mtDNA) mutations relative to others, but the mechanisms that drive these heteroplasmy differences are unknown. We find that the conserved PTEN-induced putative kinase (PINK1/PINK-1) and the E3 ubiquitin-protein ligase parkin (PDR-1), which are required for mitochondrial autophagy (mitophagy), underlie stereotyped differences in heteroplasmy of a deleterious mitochondrial genome mutation (ΔmtDNA) between major somatic tissues types in Caenorhabditis elegans. We demonstrate that tissues prone to accumulating ΔmtDNA have lower mitophagy responses than those with low mutation levels. Moreover, we show that ΔmtDNA heteroplasmy increases when proteotoxic species that are associated with neurodegenerative disease and mitophagy inhibition are overexpressed in the nervous system. These results suggest that PINK1 and parkin drive organism-wide patterns of heteroplasmy and provide evidence of a causal link between proteotoxicity, mitophagy, and mtDNA mutation levels in neurons.
    Keywords:  Alzheimer's disease; PINK1; heteroplasmy; mitochondria; mitophagy; mtDNA; parkin; polyglutamate; proteotoxicity; tau
  10. Cell Metab. 2021 Jun 01. pii: S1550-4131(21)00228-X. [Epub ahead of print]33(6): 1069-1071
      The repair and removal of damaged mitochondria is essential for sustaining cellular and tissue homeostasis. Now in Cell, Jiao et al. (2021) describe a novel mechanism of such quality control in which damaged mitochondria move to the plasma membrane where they are "packaged" and left behind the trailing edge of migrating cells.