Neurodegenerative diseases are strongly age-related and currently cannot be cured, with a surge of patient numbers in the coming decades in view of the emerging worldwide ageing population, bringing healthcare and socioeconomic challenges. Effective therapies are urgently needed, and are dependent on new etiological mechanisms. In neurons, efficient clearance of damaged mitochondria, through the highly evolutionary conserved cellular process termed mitophagy, plays a fundamental role in mitochondrial and metabolic homeostasis, energy supply, neuronal survival and health. Conversely, defective mitophagy leads to accumulation of damaged mitochondria and cellular dysfunction, contributing to ageing and age-predisposed neurodegeneration. Here, we discuss the contribution of defective mitophagy in these diseases, and underlying molecular mechanisms, and highlight novel therapeutics based on new discovered mitophagy-inducing strategies.

A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals’ memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational–experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.

No abstract

No abstract

No abstract

No abstract

Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging chemical or physical factors could trigger apoptosis that have been sensitized with pan-Bcl-2 or Bcl-xL-specific agents; Methods: We tested chemical and physical factors plus Bcl-xL-specific inhibitor A-1155463 in cells of various origins and the small roundworms (C. elegans); Results: We show that combination of a A-1155463 along with a DNA-damaging agent, 4-nitroquinoline-1-oxide (4NQO), prematurely kills cells of various origins as well as C. elegans. The synergistic effect is p53-dependent and associated with the release of Bad and Bax from Bcl-xL, which trigger mitochondrial outer membrane permeabilization. Furthermore, we found that combining Bcl-xL-specific inhibitors with various chemical compounds or physical insults also induced cell death; Conclusions: Thus, we were able to identify several biological, chemical and physical triggers of the evolutionarily conserved Bcl-xL-mediated apoptotic pathway, shedding light on strategies and targets for novel drug development.

We demonstrated recently that different viruses and transfected viral RNA or plasmid DNA killed human non-malignant cells sensitized with Bcl-xL-specific inhibitor A-1155463. Here, we show that DNA-damaging agent 4-nitroquinoline-1-oxide (4NQO) killed human non-malignant as well as malignant cells and the small roundworm C. elegans when combined with A-1155463, but not with Bcl-2-or Mcl-1-specific agents. The synergistic effect of 4NQO-A-1155463 combination was p53 dependent and was associated with the release of Bad and Bax from Bcl-xL, indicating that Bcl-xL linked DNA damage response pathways, p53 signalling and apoptosis. Other anticancer drugs (i.e. amsacrine, SN38, cisplatin, mitoxantrone, dactinomycin. dinaciclib, UCN-01, bortezomib, and S63845), as well as birth-control drug 17α-ethynylestradiol, immunosuppressant cyclosporin, antiviral agent brincidofovir, DNA binding probes MB2Py(Ac), DB2Py(4) and DBPy(5) and UV radiation also killed A-1155463-sensitized non-malignant cells. Thus, we established a method to identify physical, chemical and biological factors, which trigger Bcl-xL-mediated apoptosis. The method could be used in the development of novel anticancer therapies based on systemic Bcl-xL-specific inhibitor and local radiation, oncolytic virus infection or chemotherapy.