No abstract

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.

13Mitochondrial quality control and homeostasis is ensured by removal of the damaged 14 mitochondria involving lysosomal and proteasomal degradation mechanisms. Though 15 much remains to be elucidated, recent findings suggest important roles for endosomal 16 machinery in the elimination of damaged mitochondria. In this study, we report a novel 17 function for a FYVE-like domain containing endosomal ubiquitin ligase, CARP2 in 18 mitophagy. Our results show that endosomal CARP2 associates with damaged 19 mitochondria, and this association precedes that of Parkin, whose recruitment is known 20 to be essential for mitochondrial clearance. Association of Parkin to damaged 21 mitochondria was substantially reduced in CARP2 KO cells upon CCCP treatment. We 22 also demonstrate that Mitofusin-2 degradation, which is a prerequisite for Parkin 23 recruitment during damage, was inhibited in CARP2-deficient cells. Hence, we conclude 24 that endosomal-associated CARP2 facilitates mitophagy by regulating Parkin recruitment 25 and activation by targeting Mitofusin-2. Our study proposes a model on how 26 heterogenous endocytic machinery can interact with damaged mitochondria and unravel 27 a new mechanism for mitochondrial clearance. 28 29 30 31 32 33 Stringent quality control mechanisms ensure organelle and cellular homeostasis. 34 Signaling pathways that regulate mitochondrial quality and function are believed to play 35 critical roles in diverse physiological processes including cell survival and their 36 dysregulation results in the development of numerous pathological conditions like 37 neurological disorders, cancer and myopathies (Arun, Liu and Donmez, 2015; Ahuja, 38 2018; Porporato et al., 2018). Autophagy is a conserved intracellular catabolic process in 39 which cytoplasmic contents, including damaged mitochondria, are sequestered in double-40 membrane autophagosomes and delivered to the lysosomal compartment for 41 degradation (Dikic, 2017). Selective elimination of dysfunctional and damaged 42 mitochondria involving autophagic machinery and lysosomes is known as mitophagy 43 (Montava-Garriga and Ganley, 2020). 44 Though cells can employ various other cellular tools like ESCRT machinery (Hammerling 45 et al., 2017), MDVs (Mitochondrial Derived Vesicles) (Sugiura et al., 2014; McLelland et 46 al., 2016) etc., to remove mitochondrial contents, mitophagy mediated by PINK1/Parkin 47 is relatively well studied (Narendra et al., 2008(Narendra et al., , 2010 Durcan and Fon, 2015). In 48 depolarized mitochondria, PINK1 accumulated on the outer mitochondrial membrane 49 phosphorylates Parkin which in turn pleiotropically ubiquitinates Mfn2 resulting in its 50 degradation. Mfn2 degradation mediated by Parkin is believed to be a critical step in 51 Parkin stabilization and mitophagy, as Mfn2 regulates physical attachment of 52 mitochondria to ER. Many details of the sequence of events involved in Parkin 53 recruitment, stabilization and identity of proteins are not available. 54 Recent reports, however, suggested a role...

Mitochondrial quality control and homeostasis is ensured by removal of the damaged mitochondria involving lysosomal and proteasomal degradation mechanisms. Though much remains to be elucidated, recent findings suggest important roles for endosomal machinery in the elimination of damaged mitochondria. In this study, we report a novel function for a FYVE-like domain containing endosomal ubiquitin ligase, CARP2 in mitophagy. Our results show that endosomal CARP2 associates with damaged mitochondria, and this association precedes that of Parkin, whose recruitment is known to be essential for mitochondrial clearance. Association of Parkin to damaged mitochondria was substantially reduced in CARP2 KO cells upon CCCP treatment. We also demonstrate that Mitofusin-2 degradation, which is a prerequisite for Parkin recruitment during damage, was inhibited in CARP2-deficient cells. Hence, we conclude that endosomal-associated CARP2 facilitates mitophagy by regulating Parkin recruitment and activation by targeting Mitofusin-2. Our study proposes a model on how heterogenous endocytic machinery can interact with damaged mitochondria and unravel a new mechanism for mitochondrial clearance.