Velikkakath, A. K. G. | Search bioRxiv

bioRxiv2020

Endosomes facilitate mitochondrial clearance by enhancing Mfn2 degradation and subsequent Parkin recruitment

Mutations in ubiquitin ligase Parkin are associated with Parkinsons disease and defective mitophagy. Conceptually, Parkin-dependent mitophagy is classified into two phases; 1. Parkin recruits to and ubiquitinates mitochondrial proteins, 2. Formation of autophagosome membrane, sequestering mitochondria for degradation. Recently, endosomal machineries were reported to contribute to the later stage for membrane assembly. We report a role for endosomes in the events upstream of phase 1. We demonstrate that an endosomal ubiquitin ligase CARP2 associates with damaged mitochondria, and this association precedes that of Parkin. CARP2 interacts with Parkin, and stable recruitment of Parkin to damaged mitochondria was substantially reduced in CARP2 KO cells. Our study unravels a novel role of endosomes in modulating upstream pathways of Parkin-dependent mitophagy initiation.

cell biology↗

bioRxiv2019

Paradigm of Vanadium pentoxide nanoparticle-induced autophagy and apoptosis in triple-negative breast cancer cells

Chemo-resistance remains the main hurdle to cancer therapy, challenging the improvement of clinical outcomes in cancer patients. Therefore, exploratory studies to address chemo-resistance through various approaches are highly rewarding. Nanomedicine is a promising recent advancement in this direction. Comprehensive studies to understand the precise molecular interactions of nanomaterials is necessary to validate their specific "nano induced" effects. Here, we illustrate in detail the specific biological interactions of vanadium pentoxide nanoparticles (VnNp) on triple-negative breast cancer cells and provide initial insights towards its potential in breast cancer management at the cellular level. VnNp shows a time-dependent anti-oxidant and pro-oxidant property in vitro. These nanoparticles specifically accumulate in the lysosomes and mitochondria, modulate various cellular processes including impaired lysosomal function, mitochondrial damage, and induce autophagy. At more extended periods, VnNp influences cell cycle arrest and inhibits cell migration potentiating the onset of apoptosis. Preliminary in vivo studies, on exposing healthy Swiss albino mice to VnNp demonstrated normal blood parameters, organ distribution, and tissue redox balance which further indicated the absence of any adverse organ toxicity. Hence, we foresee tumor-targeting VnNp as a potential drug molecule for future cancer management.

scientific communication and education↗