bims-mitlys Biomed News
on Mitochondria and Lysosomes
Issue of 2021‒06‒20
four papers selected by
Nicoletta Plotegher
University of Padua


  1. Mol Aspects Med. 2021 Jun 12. pii: S0098-2997(21)00032-7. [Epub ahead of print] 100972
      Autophagy is the process by which cells can selectively or non-selectively remove damaged proteins and organelles. As the cell's main means of sequestering damaged mitochondria for removal, mitophagy is central to cellular function and survival. Research on autophagy and mitochondrial quality control has increased exponentially in relation to the pathogenesis of numerous disease conditions, from cancer and immune diseases to chronic neurodegenerative diseases like Parkinson's disease (PD). Understanding how components of the autophagic/mitophagic machinery are affected during disease, as well as the contextual relationship of autophagy with determining neuronal health and function, is essential to the goal of designing therapies for human disease. In this review, we will summarize key signaling molecules that consign damaged mitochondria for autophagic degradation, describe the relationship of genes linked to PD to autophagy/mitophagy dysfunction, and discuss additional roles of both mitochondrial and cytosolic pools of PTEN-induced kinase 1 (PINK1) in mitochondrial homeostasis, dendritic morphogenesis and inflammation.
    Keywords:  Autophagy; Mitochondria; Mitophagy; Neurodegeneration; PINK1; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.mam.2021.100972
  2. Mol Biol Cell. 2021 Jun 16. mbcE21030097
      Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and mitochondria are emerging as critical hubs for diverse cellular events, and alterations in the extent of these contacts are linked to neurodegenerative diseases. However, the mechanisms that control ER-mitochondrial interactions are so far elusive. Here, we demonstrate a key role of vacuolar protein sorting-associated protein 13D (VPS13D) in the negative regulation of ER-mitochondrial MCSs. VPS13D suppression results in extensive ER-mitochondrial tethering, a phenotype that can be substantially rescued by suppression of the tethering proteins VAPB and PTPIP51. VPS13D interacts with valosin-containing protein (VCP/p97) to control the level of ER-resident VAPB at contacts. VPS13D is required for the stability of p97. Functionally, VPS13D suppression leads to severe defects in the mitochondrial morphology, mitochondrial cellular distribution and mitochondrial DNA synthesis. Together our results suggest that VPS13D negatively regulates the ER-mitochondrial MCSs partially through its interactions with VCP/p97. [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E21-03-0097
  3. Transl Neurodegener. 2021 Jun 15. 10(1): 19
      BACKGROUND: Mitochondrial dysfunction plays a prominent role in the pathogenesis of Parkinson's disease (PD), and several genes linked to familial PD, including PINK1 (encoding PTEN-induced putative kinase 1 [PINK1]) and PARK2 (encoding the E3 ubiquitin ligase Parkin), are directly involved in processes such as mitophagy that maintain mitochondrial health. The dominant p.D620N variant of vacuolar protein sorting 35 ortholog (VPS35) gene is also associated with familial PD but has not been functionally connected to PINK1 and PARK2.METHODS: To better mimic and study the patient situation, we used CRISPR-Cas9 to generate heterozygous human SH-SY5Y cells carrying the PD-associated D620N variant of VPS35. These cells were treated with a protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP) to induce the PINK1/Parkin-mediated mitophagy, which was assessed using biochemical and microscopy approaches.
    RESULTS: Mitochondria in the VPS35-D620N cells exhibited reduced mitochondrial membrane potential and appeared to already be damaged at steady state. As a result, the mitochondria of these cells were desensitized to the CCCP-induced collapse in mitochondrial potential, as they displayed altered fragmentation and were unable to accumulate PINK1 at their surface upon this insult. Consequently, Parkin recruitment to the cell surface was inhibited and initiation of the PINK1/Parkin-dependent mitophagy was impaired.
    CONCLUSION: Our findings extend the pool of evidence that the p.D620N mutation of VPS35 causes mitochondrial dysfunction and suggest a converging pathogenic mechanism among VPS35, PINK1 and Parkin in PD.
    Keywords:  Mitochondrial membrane potential; Mitophagy; PINK1; Parkin; Parkinson’s disease; VPS35
    DOI:  https://doi.org/10.1186/s40035-021-00243-4
  4. Neurochem Int. 2021 Jun 08. pii: S0197-0186(21)00141-8. [Epub ahead of print]148 105095
      Mitochondria are semi-autonomous organelle staging a crucial role in cellular stress response, energy metabolism and cell survival. Maintaining mitochondrial quality control is very important for its homeostasis. Pathological conditions such as oxidative stress and neurodegeneration, disrupt this quality control, and involvement of genetic and epigenetic materials in this disruption have been reported. These regulatory factors trigger mitochondrial imbalance, as seen in many neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. The dynamic regulatory pathways i.e. mitophagy, biogenesis, permeability pore transitioning, fusion-fission are affected as a consequence and have been reviewed in this article. Moreover, several epigenetic mechanisms such as DNA methylation and histone modulation participating in such neurological disorders have also been discussed. Apart from it, therapeutic approaches targeting mitochondrial quality control have been tremendously explored showing ameliorative effects for these diseases, and have been discussed here with a novel perspective.
    Keywords:  Biogenesis; DNA methylation; Histone acetylation; Mitochondrial quality control; Mitophagy; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.neuint.2021.105095