bims-mitlys Biomed News
on Mitochondria and Lysosomes
Issue of 2021‒08‒22
seven papers selected by
Nicoletta Plotegher
University of Padua

  1. Cell Calcium. 2021 Aug 05. pii: S0143-4160(21)00107-X. [Epub ahead of print]98 102453
      Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are morpho-functional units, formed at the loci of close apposition of the ER-forming endomembrane and outer mitochondrial membrane (OMM). These sites contribute to fundamental cellular processes including lipid biosynthesis, autophagy, apoptosis, ER-stress and calcium (Ca2+) signalling. At MERCS, Ca2+ ions are transferred from the ER directly to mitochondria through a core protein complex composed of inositol-1,4,5 trisphosphate receptor (InsP3R), voltage-gated anion channel 1 (VDAC1), mitochondrial calcium uniporter (MCU) and adaptor protein glucose-regulated protein 75 (Grp75); this complex is regulated by several associated proteins. Deregulation of ER-mitochondria Ca2+ transfer contributes to pathogenesis of neurodegenerative and other diseases. The efficacy of Ca2+ transfer between ER and mitochondria depends on the protein composition of MERCS, which controls ER-mitochondria interaction regulating, for example, the transversal distance between ER membrane and OMM and the extension of the longitudinal interface between ER and mitochondria. These parameters are altered in neurodegeneration. Here we overview the ER and mitochondrial Ca2+ homeostasis, the composition of ER-mitochondrial Ca2+ transfer machinery and alterations of the ER-mitochondria Ca2+ transfer in three major neurodegenerative diseases: motor neurone diseases, Parkinson disease and Alzheimer's disease.
    Keywords:  Alzheimer's disease; Amyotrophic lateral sclerosis; Endoplasmic reticulum; Mitochondria; Mitochondria-ER contact sites; Motor neurone disease; Parkinson's disease
  2. Int Rev Cell Mol Biol. 2021 ;pii: S1937-6448(21)00038-1. [Epub ahead of print]363 49-121
      Cancer is a leading cause of death worldwide. All major tumor suppressors and oncogenes are now recognized to have fundamental connections with metabolic pathways. A hallmark feature of cancer cells is a reprogramming of their metabolism even when nutrients are available. Increasing evidence indicates that most cancer cells rely on mitochondrial metabolism to sustain their energetic and biosynthetic demands. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca2+) storage organelle in mammalian cells, through special domains known as mitochondria-ER contact sites (MERCS). In this domain, the release of Ca2+ from the ER is mainly regulated by inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), a family of Ca2+ release channels activated by the ligand IP3. IP3R mediated Ca2+ release is transferred to mitochondria through the mitochondrial Ca2+ uniporter (MCU). Once in the mitochondrial matrix, Ca2+ activates several proteins that stimulate mitochondrial performance. The role of IP3R and MCU in cancer, as well as the other proteins that enable the Ca2+ communication between these two organelles is just beginning to be understood. Here, we describe the function of the main players of the ER mitochondrial Ca2+ communication and discuss how this particular signal may contribute to the rise and development of cancer traits.
    Keywords:  Cancer hallmarks; IP3R; MCUC; Metabolism; Mitochondria-associated membranes (MAMs)
  3. Cell Death Dis. 2021 Aug 16. 12(9): 794
      Cellular therapy exerts profound therapeutic potential for curing a broad spectrum of diseases. Adult stem cells reside within a specified dynamic niche in vivo, which is essential for continuous tissue homeostatic maintenance through balancing self-renewal with lineage selection. Meanwhile, adult stem cells may be multipotent or unipotent, and are present in both quiescent and actively dividing states in vivo of the mammalians, which may switch to each other state in response to biophysical cues through mitochondria-mediated mechanisms, such as alterations in mitochondrial respiration and metabolism. In general, stem cells facilitate tissue repair after tissue-specific homing through various mechanisms, including immunomodulation of local microenvironment, differentiation into functional cells, cell "empowerment" via paracrine secretion, immunoregulation, and intercellular mitochondrial transfer. Interestingly, cell-source-specific features have been reported between different tissue-derived adult stem cells with distinct functional properties due to the different microenvironments in vivo, as well as differential functional properties in different tissue-derived stem cell-derived extracellular vehicles, mitochondrial metabolism, and mitochondrial transfer capacity. Here, we summarized the current understanding on roles of mitochondrial dynamics during stem cell homeostasis and aging, and lineage-specific differentiation. Also, we proposed potential unique mitochondrial molecular signature features between different source-derived stem cells and potential associations between stem cell aging and mitochondria-endoplasmic reticulum (ER) communication, as well as potential novel strategies for anti-aging intervention and healthy aging.
  4. Neurobiol Dis. 2021 Aug 11. pii: S0969-9961(21)00224-2. [Epub ahead of print] 105475
      From the first illustrations of neuronal morphology by Ramón y Cajal to the recent three-dimensional reconstruction of synaptic connections, the development of modern neuroscience has greatly benefited from breakthroughs in imaging technology. This also applies specifically to the study of neurodegenerative diseases. Much of the research into these diseases relies on the direct visualisation of intracellular structures and their dynamics in degenerating neural cells, which cannot be fully resolved by diffraction-limited microscopes. Progress in the field has therefore been closely linked to the development of super-resolution imaging methods. Their application has greatly advanced our understanding of disease mechanisms, ranging from the structural progression of protein aggregates to defects in organelle morphology. Recent super-resolution studies have specifically implicated the disruption of inter-organelle interactions in multiple neurodegenerative diseases. In this article, we describe some of the key super-resolution techniques that have contributed to this field. We then discuss work to visualise changes in the structure and dynamics of organelles and associated dysfunctions. Finally, we consider what future developments in imaging technology may further our knowledge of these processes.
  5. Int Rev Cell Mol Biol. 2021 ;pii: S1937-6448(21)00075-7. [Epub ahead of print]363 169-202
      Glucotoxicity-induced β-cell dysfunction in type 2 diabetes is associated with alterations of mitochondria and the endoplasmic reticulum (ER). Mitochondria and ER form a network in cells that controls cell function and fate. Mitochondria of the pancreatic β cell play a central role in the secretion of insulin in response to glucose through their ability to produce ATP. Both organelles interact at contact sites, defined as mitochondria-associated membranes (MAMs), which were recently implicated in the regulation of glucose homeostasis. Here, we review MAM functions in the cell and we focus on the crosstalk between the ER and Mitochondria in the context of T2D, highlighting the pivotal role played by MAMs especially in β cells through inter-organelle calcium exchange and glucotoxicity-associated β cell dysfunction.
    Keywords:  Calcium; ER; Glucotoxicity; MAMs; Mitochondria; Type 2 Diabetes; β cells
  6. J Mol Med (Berl). 2021 Aug 16.
      Autophagy is a well-known cell-survival strategy orchestrated by a conserved set of proteins. It equips the cells with mechanisms to attain homeostasis during unfavorable conditions such as stress by breaking down the cellular components and reusing them for energy as well as for building new components required for survival. A basal level of autophagy is required for achieving homeostasis under normal conditions through regular turnover of macromolecules and organelles. Initiation of autophagy is regulated by two key components of the nutrient/energy sensor pathways; mammalian target of rapamycin 1 (mTORC1) and AMP-activated kinase (AMPK). Under energy-deprived conditions, AMPK is activated triggering autophagy, whereas, in nutrient-rich conditions, the growth-promoting kinase mTORC1 is activated inhibiting autophagy. Thus, the reciprocal regulation of autophagy by AMPK and mTORC1 defines a fundamental mechanism by which cells respond to nutrient availability. Interestingly, cytoplasmic calcium is also found to be an activator of AMPK and autophagy through a calmodulin/CaMKKβ pathway. However, the physiological significance of the regulation of autophagy by cytoplasmic calcium is currently unclear. This review focuses on the current understanding of the mechanism of autophagy and its regulation by AMPK.
    Keywords:  AMPK; Autophagy; CaMKKβ; Calcium; Energy homeostasis; LKB1; mTORC1
  7. Kidney Dis (Basel). 2021 Jul;7(4): 278-292
      Introduction: Acute kidney injury (AKI) is at a high prevalence in hospitalized patients, especially in those receiving chemotherapy. Cisplatin is the most widely used chemotherapy drug; however, with its side effects that include nephrotoxicity, it also exhibits a risk of inducing AKI. Importantly, recent studies have shown that autophagy plays a protective role in cisplatin-induced AKI. However, therapeutic strategies and candidate drugs for inducing activation of autophagy remain limited.Methods: In the present study, we adopted a novel candidate drug from a deep sea-derived Penicillium strain, penicilliumin B, to testify its protective role in cisplatin-induced renal tubular cell injury.
    Results: Penicilliumin B exhibited protection against cisplatin-induced apoptosis in cultured renal tubular epithelial cells and in cisplatin-treated mice. Moreover, penicilliumin B maintained normal mitochondrial morphology and inhibited the production of mitochondrial reactive oxygen species. Further studies demonstrated that penicilliumin B enhanced autophagic flux, promoted the activation of multiple autophagy-related proteins, such as mTOR, Beclin-1, ATG5, PINK1, and LC3B, and induced the degradation of p62. Interestingly, we also found penicilliumin B triggered phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK), which is an upstream inducer of nearly all autophagy pathways and also an activator of mitochondrial biogenesis. These results suggest that AMPK may represent an activated site of penicilliumin B. Consistently, compound C, an AMPK inhibitor, significantly blocked the protective effects of penicilliumin B on mitochondria and apoptotic inhibition.
    Conclusion: Taken together, our findings indicate that penicilliumin B represents a novel AMPK activator that may provide protection against renal tubular cell apoptosis through activation of AMPK-induced autophagy and mitochondrial biogenesis.
    Keywords:  Adenosine 5′-monophosphate-activated protein kinase; Apoptosis; Autophagy; Cisplatin; Penicilliumin B