bims-mitlys Biomed News
on Mitochondria and Lysosomes
Issue of 2021‒08‒15
six papers selected by
Nicoletta Plotegher
University of Padua

  1. Food Chem Toxicol. 2021 Aug 08. pii: S0278-6915(21)00518-4. [Epub ahead of print]156 112485
      Aluminum (Al) is known to be hepatotoxic. Oxidative stress is the main mechanism of liver injury caused by Al, and can also lead to mitochondrial damage. Mitochondrial damage is a prerequisite for mitochondrial quality control (MQC) dysregulation. Parkin can activate MQC and maintain mitochondrial homeostasis. However, the role of Parkin-mediated MQC in Al-induced liver damage has not been elucidated. In this study, forty male wild type (WT) C57BL/6N mice were treated with 0, 44.825, 89.65 or 179.3 mg/kg body weight AlCl3 in drinking water for 90 days, respectively. We found that Al induced mitophagy and disrupted mitochondrial dynamics and mitochondrial biogenesis. Then, twenty male WT C57BL/6N mice and twenty male Parkin knockout (Parkin-/-) C57BL/6N mice were divided into four groups and treated with 0, 89.65, 0, 89.65 mg/kg body weight AlCl3 in drinking water for 90 days, respectively. We found that Parkin-/- inhibited mitophagy and further disrupted mitochondrial dynamics and mitochondrial biogenesis. These results indicated that Parkin-mediated MQC could be disrupted by Al and protected against Al-induced liver damage.
    Keywords:  Aluminum (Al); Liver; Mice; Mitochondrial quality control; Parkin
  2. PLoS Genet. 2021 Aug 12. 17(8): e1009731
      A healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation.
  3. Life Sci. 2021 Aug 10. pii: S0024-3205(21)00863-8. [Epub ahead of print] 119876
      Mitochondria are biosynthetic, bioenergetic, and signaling organelles which are critical for physiological adaptations and cellular stress responses to the environment. Various endogenous and environmental stress affects critical processes in mitochondrial homeostasis such as oxidative phosphorylation, biogenesis, mitochondrial redox system which leads to the formation of reactive oxygen species (ROS) and free radicals. The state of function of the mitochondrion is particularly dependent on the dynamic balance between mitochondrial biogenesis, fusion and fission, and degradation of damaged mitochondria by mitophagy. Increasing evidence has suggested a prominent role of mitochondrial dysfunction in the onset and progression of various lung pathologies, ranging from acute to chronic disorders. In this comprehensive review, we discuss the emerging findings of multifaceted regulations of mitochondrial dynamics and mitophagy in normal lung homeostasis as well as the prominence of mitochondrial dysfunction as a determining factor in different lung disorders such as lung cancer, COPD, IPF, ALI/ARDS, BPD, and asthma. The review will contribute to the existing understanding of critical molecular machinery regulating mitochondrial dynamic state during these pathological states. Furthermore, we have also highlighted various molecular checkpoints involved in mitochondrial dynamics, which may serve as hopeful therapeutic targets for the development of potential therapies for these lung disorders.
    Keywords:  Lung disorders; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mitophagy
  4. Cureus. 2021 Aug;13(8): e16973
      The GTP-binding protein, Rho, plays a significant role in the cellular pathology of Parkinson's disease. The downstream effector of Rho, Rho-associated kinase (ROCK), performs several functions, including microglial inflammatory response and enhanced Parkin-mediated mitophagy. Its inhibition shows neuroprotective effects in carried studies. Parkinson's disease pathology also rests on incomplete removal of damaged mitochondria, leading to neuronal impairment. ROCK has different isoforms, inhibition of which have been shown to decrease the adverse changes in microglia. There has also been evidence of a decreased release of inflammatory cytokines and a reduction in degradation of dopaminergic neurons on the addition of ROCK inhibitors. Additionally, ROCK inhibitors have recently been shown to increase the activity of hexokinase 2 (HK2), relocating it to mitochondria, and therefore leading to upregulated mitochondrial targeting. Understanding the cellular basis of ROCK activity and its inhibition may help us advance in creating new strategies for the treatment of Parkinson's disease.
    Keywords:  dopaminergic survival; fasudil; hexokinase; mitophagy; parkin; parkinson’s disease; pink1; rho-associated protein kinase; rock; substantia nigra
  5. Sci Rep. 2021 Aug 13. 11(1): 16512
      Decreased mitochondrial membrane potential in cerebrospinal fluid (CSF) was observed in patients with subarachnoid hemorrhage (SAH) accompanied by delayed cerebral ischemia (DCI). However, whether abnormal mechanisms of mitochondria are associated with the development of DCI has not been reported yet. Under cerebral ischemia, mitochondria can transfer into the extracellular space. Mitochondrial dysfunction can aggravate neurologic complications. The objective of this study was to evaluate whether mitochondrial dysfunction might be associated with autophagy and mitophagy in CSF cells to provide possible insight into DCI pathogenesis. CSF samples were collected from 56 SAH patients (DCI, n = 21; and non-DCI, n = 35). We analyzed CSF cells using autophagy and mitophagy markers (DAPK1, BNIP3L, BAX, PINK1, ULK1, and NDP52) via qRT-PCR and western blotting of proteins (BECN1, LC3, and p62). Confocal microscopy and immunogold staining were performed to demonstrate the differentially expression of markers within dysfunctional mitochondria. Significant induction of autophagic flux with accumulation of autophagic vacuoles, increased expression of BECN1, LC3-II, and p62 degradation were observed during DCI. Compared to non-DCI patients, DCI patients showed significantly increased mRNA expression levels (2-ΔCt) of DAPK1, BNIP3L, and PINK1, but not BAX, ULK1, or NDP52. Multivariable logistic regression analysis revealed that Hunt and Hess grade ≥ IV (p = 0.023), DAPK1 (p = 0.003), and BNIP3L (p = 0.039) were related to DCI. Increased mitochondrial dysfunction associated with autophagy and mitophagy could play an important role in DCI pathogenesis.
  6. Oxid Med Cell Longev. 2021 ;2021 7356266
      Cerebral ischemia-reperfusion (I-R) transiently increased autophagy by producing excessively reactive oxygen species (ROS); on the other hand, activated autophagy would remove ROS-damaged mitochondria and proteins, which led to cell survival. However, the regulation mechanism of autophagy activity during cerebral I-R is still unclear. In this study, we found that deficiency of the TRPM2 channel which is a ROS sensor significantly decreased I-R-induced neuronal damage. I-R transiently increased autophagy activity both in vitro and in vivo. More importantly, TRPM2 deficiency decreased I-R-induced neurological deficit score and infarct volume. Interestingly, our results indicated that TRPM2 deficiency could further activate AMPK rather than Beclin1 activity, suggesting that TRPM2 inhibits autophagy by regulating the AMPK/mTOR pathway in I-R. In conclusion, our study reveals that ROS-activated TRPM2 inhibits autophagy by downregulating the AMPK/mTOR pathway, which results in neuronal death induced by cerebral I-R, further supporting that TRPM2 might be a potential drug target for cerebral ischemic injury therapy.