bims-mitlys Biomed News
on Mitochondria and Lysosomes
Issue of 2021‒05‒23
eight papers selected by
Nicoletta Plotegher
University of Padua

  1. Curr Biol. 2021 May 14. pii: S0960-9822(21)00609-6. [Epub ahead of print]
      Mutations in Vps13D cause defects in autophagy, clearance of mitochondria, and human movement disorders. Here, we discover that Vps13D functions in a pathway downstream of Vmp1 and upstream of Marf/Mfn2. Like vps13d, vmp1 mutant cells exhibit defects in autophagy, mitochondrial size, and clearance. Through the relationship between vmp1 and vps13d, we reveal a novel role for Vps13D in the regulation of mitochondria and endoplasmic reticulum (ER) contact. Significantly, the function of Vps13D in mitochondria and ER contact is conserved between fly and human cells, including fibroblasts derived from patients suffering from VPS13D mutation-associated neurological symptoms. vps13d mutants have increased levels of Marf/MFN2, a regulator of mitochondrial fusion. Importantly, loss of marf/MFN2 suppresses vps13d mutant phenotypes, including mitochondria and ER contact. These findings indicate that Vps13d functions at a regulatory point between mitochondria and ER contact, mitochondrial fusion and autophagy, and help to explain how Vps13D contributes to disease.
    Keywords:  Drosophila; Vmp1; Vps13D; autophagy; membrane contact; mitochondria
  2. J Cell Sci. 2020 Jan 01. pii: jcs.237917. [Epub ahead of print]
      Heme is a cofactor and signaling molecule that is essential for much of aerobic life. All heme-dependent processes in eukaryotes require that heme is trafficked from its site of synthesis in the mitochondria to hemoproteins located throughout the cell. However, the mechanisms governing the mobilization of heme out of the mitochondria, and the spatio-temporal dynamics of these processes, are poorly understood. Herein, using genetically encoded fluorescent heme sensors, we developed a live cell assay to monitor heme distribution dynamics between the mitochondrial inner-membrane, where heme is synthesized, and the mitochondrial matrix, cytosol, and nucleus. Surprisingly, heme trafficking to the nucleus is ∼25% faster than to the cytosol or mitochondrial matrix, which are nearly identical, potentially supporting a role for heme as a mitochondrial-nuclear retrograde signal. Moreover, we discovered that the heme synthetic enzyme, 5-aminolevulinic acid synthase (ALAS), and GTPases in control of the mitochondrial dynamics machinery, Mgm1 and Dnm1, and ER contact sites, Gem1, regulate the flow of heme between the mitochondria and nucleus. Overall, our results indicate that there are parallel pathways for the distribution of bioavailable heme.
    Keywords:  Heme; Heme transport; Mitochondrial dynamics; Yeast
  3. J Agric Food Chem. 2021 May 21.
      The pollution of aluminum (Al) in agricultural production and its wide application in food processing greatly increase the chance of human and animal exposure. Al can accumulate in bone and cause bone diseases by inducing oxidative stress. Mitophagy can maintain normal cell function by degrading damaged mitochondria and scavenging reactive oxygen species. However, the role of mitophagy in the bone impairment caused by Al is unknown. In this study, we demonstrated that PTEN induced putative kinase 1 (PINK1)/ E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy was activated in the bone impairment caused by Al in vivo. Then, the Al-induced mitophagy in Parkin-deficient mice and MC3T3-E1 cells were decreased. Meanwhile, Parkin deficiency exacerbated the bone impairment, mitochondrial damage, and oxidative stress under Al exposure, both in vivo and in vitro. In general, the results reveal that Al exposure can activate PINK1/Parkin-mediated mitophagy, and the PINK1/Parkin-mediated mitophagy plays a protective role in the bone impairment caused by Al.
    Keywords:  Parkin; aluminum; bone impairment; mitophagy; oxidative stress
  4. Food Funct. 2021 May 17.
      This study investigated the toxic effects of trans,trans-2,4-decadienal (tt-DDE) on vascular endothelial cells as well as the underlying mechanisms involved. Human umbilical vascular endothelial cells (HUVECs) were treated with different concentrations of tt-DDE for 24 h, and cell viability, colony formation ability, apoptosis, mitochondrial function and autophagy pathway were determined. The results showed that tt-DDE dose-dependently inhibited cell viability and colony formation, and increased lactate dehydrogenase (LDH) release and apoptosis in HUVECs. Besides, tt-DDE exposure induced extensive mitochondrial damage, as evidenced by the decreased mitochondrial DNA copy number, ATP synthesis, and mitochondrial membrane potential, and increased mitochondrial reactive oxygen species (ROS) production and cytochrome c release from mitochondria. tt-DDE also induced mitochondrial fragmentation and fission by increasing DNM1L protein expression and DNM1L mitochondrial translocation. Additionally, tt-DDE treatment resulted in the blockage of autophagic flux and accumulation of autophagosomes in endothelial cells. Further investigation revealed that the inhibition of autophagy by 3-methyladenine aggravated tt-DDE-induced mitochondrial dysfunction and cell injury. However, scavenging of ROS by N-acetyl-l-cysteine (NAC) significantly prevented tt-DDE-induced mitochondrial damage, autophagy dysfunction, and cell injury. These data indicated that tt-DDE induced endothelial cell injury through impairing mitochondrial function and autophagic flux.
  5. Cell Mol Biol Lett. 2021 May 18. 26(1): 18
      BACKGROUND: Mammalian/mechanistic target of rapamycin (mTOR) complexes are essential for cell proliferation, growth, differentiation, and survival. mTORC1 hyperactivation occurs in the tuberous sclerosis complex (TSC). mTORC1 localizes to the surface of lysosomes, where Rheb activates it. However, mTOR was also found on the endoplasmic reticulum (ER) and Golgi apparatus (GA). Recent studies showed that the same inputs regulate ER-to-GA cargo transport and mTORC1 (e.g., the level of amino acids or energy status of the cell). Nonetheless, it remains unknown whether mTOR contributes to the regulation of cargo passage through the secretory pathway.METHODS: The retention using selective hooks (RUSH) approach was used to image movement of model cargo (VSVg) between the ER and GA in various cell lines in which mTOR complexes were inhibited. We also investigated VSVg trafficking in TSC patient fibroblasts.
    RESULTS: We found that mTOR inhibition led to the overall enhancement of VSVg transport through the secretory pathway in PC12 cells and primary human fibroblasts. Also, in TSC1-deficient cells, VSVg transport was enhanced.
    CONCLUSIONS: Altogether, these data indicate the involvement of mTOR in the regulation of ER-to-GA cargo transport and suggest that impairments in exocytosis may be an additional cellular process that is disturbed in TSC.
    Keywords:  Endoplasmic reticulum; Golgi apparatus; MTOR; Retention using selective hooks; Tuberous sclerosis complex; VSVg
  6. J Cell Sci. 2020 Jan 01. pii: jcs.250241. [Epub ahead of print]
      Defective intracellular trafficking and export of microRNAs have been observed in growth retarded mammalian cells having impaired mitochondrial potential and dynamics. Uncoupling Protein 2 mediated depolarization of mitochondrial membrane also results in progressive sequestration of microRNAs with polysomes and lowered their release via extracellular vesicles. Interestingly, impaired miRNA-trafficking process in growth retarded human cells could be reversed in presence of Genipin an inhibitor of Uncoupling Protein 2. Mitochondrial detethering of endoplasmic reticulum, observed in mitochondria depolarized cells, found to be responsible for defective compartmentalization of translation initiation factor eIF4E to endoplasmic reticulum attached polysomes. It causes retarded translation process accompanied by enhanced retention of miRNAs and target mRNAs with endoplasmic reticulum attached polysomes to restrict extracellular export of miRNAs. Reduced compartment specific activity of mTORC1 complex, the master regulator of protein synthesis, in mitochondria defective or ER- detethered cells, causes reduced phosphorylation of eIF4E-BP1 to prevent eIF-4E targeting to ER attached polysome and microRNA export. These data suggest how mitochondrial membrane potential and dynamics, by affecting mTORC1 activity and compartmentalization, determine sub-cellular localization and export of microRNAs.
    Keywords:  EIF4E and mTORC1; Exosomes; Extracellular vesicles; MiRNA; Mitochondria; P-body; Polysome; Processing bodies
  7. EMBO Mol Med. 2021 May 16. e13074
      The phospholamban (PLN) p.Arg14del mutation causes dilated cardiomyopathy, with the molecular disease mechanisms incompletely understood. Patient dermal fibroblasts were reprogrammed to hiPSC, isogenic controls were established by CRISPR/Cas9, and cardiomyocytes were differentiated. Mutant cardiomyocytes revealed significantly prolonged Ca2+ transient decay time, Ca2+ -load dependent irregular beating pattern, and lower force. Proteomic analysis revealed less endoplasmic reticulum (ER) and ribosomal and mitochondrial proteins. Electron microscopy showed dilation of the ER and large lipid droplets in close association with mitochondria. Follow-up experiments confirmed impairment of the ER/mitochondria compartment. PLN p.Arg14del end-stage heart failure samples revealed perinuclear aggregates positive for ER marker proteins and oxidative stress in comparison with ischemic heart failure and non-failing donor heart samples. Transduction of PLN p.Arg14del EHTs with the Ca2+ -binding proteins GCaMP6f or parvalbumin improved the disease phenotype. This study identified impairment of the ER/mitochondria compartment without SR dysfunction as a novel disease mechanism underlying PLN p.Arg14del cardiomyopathy. The pathology was improved by Ca2+ -scavenging, suggesting impaired local Ca2+ cycling as an important disease culprit.
    Keywords:  endoplasmic reticulum; engineered heart tissue; human-induced pluripotent stem cells; mitochondria; phospholamban p.Arg14del
  8. J Alzheimers Dis. 2021 May 11.
      Silent information-regulated transcription factor 1 (SIRT1) is the most prominent and widely studied member of the sirtuins (a family of mammalian class III histone deacetylases). It is a nuclear protein, and the deacetylation of the peroxisome proliferator-activated receptor coactivator-1 has been extensively implicated in metabolic control and mitochondrial biogenesis and is the basis for studies into its involvement in caloric restriction and its effects on lifespan. The present study discusses the potentially protective mechanism of SIRT1 in the regulation of the mitochondrial biogenesis and autophagy involved in the modulation of Alzheimer's disease, which may be correlated with the role of SIRT1 in affecting neuronal morphology, learning, and memory during development; regulating metabolism; counteracting stress responses; and maintaining genomic stability. Drugs that activate SIRT1 may offer a promising approach to treating Alzheimer's disease.
    Keywords:  Alzheimer’s disease; SIRT1; mitochondrial autophagy; protective mechanism