Biology of the Cell最新文献

Background Information

Various types of stress initially induce a state of cardiac hypertrophy (CH) in the heart. But, persistent escalation of cardiac stress leads to progression from an adaptive physiological to a maladaptive pathological state. So, elucidating molecular mechanisms that can attenuate CH is imperative in developing cardiac therapies. Previously, we showed that Prohibitin1 (PHB1) has a protective role in CH-induced oxidative stress. Nevertheless, it is unclear how PHB1, a mitochondrial protein, has a protective role in CH. Therefore, we hypothesized that PHB1 maintains mitochondrial quality in CH. To test this hypothesis, we used Isoproterenol (ISO) to induce CH in H9C2 cells overexpressing PHB1 and elucidated mitochondrial quality control pathways.

Results

We found that overexpressing PHB1 attenuates ISO-induced CH and restores mitochondrial morphology in H9C2 cells. In addition, PHB1 blocks the pro-hypertrophic IGF1R/AKT pathway and restores the mitochondrial membrane polarization in ISO-treated cells. We observed that overexpressing PHB1 promotes mitochondrial biogenesis, improves mitochondrial respiratory capacity, and triggers mitophagy.

Conclusion

We conclude that PHB1 maintains mitochondrial quality in ISO-induced CH in H9C2 cells.

Significance

Based on our results, we suggest that small molecules that induce PHB1 in cardiac cells may prove beneficial in developing cardiac therapies.

Negative-sense, single-stranded RNA (-ssRNA) viruses comprise some of the deadliest human pathogens (Ebola, rabies, influenza A viruses etc.). Developing therapeutic tools relies on a better understanding of their multiplication cycle. For these viruses, the genome replication and transcription activities most-often segregate in membrane-less environments called inclusion bodies (IBs) or viral factories. These “organelles” usually locate far from the cell surface from where new virions are released, and -ssRNA viruses do not encode for transport factors. The efficient trafficking of the genome progeny toward the cell surface is most often ensured by mechanisms co-opting the cellular machineries.

In this review, for each -ssRNA viral family, we cover the methods employed to characterize these host-virus interactions, the strategies used by the viruses to promote the virus genome transport, and the current gaps in the literature. Finally, we highlight how Rab11 has emerged as a target of choice for the intracellular transport of -ssRNA virus genomes.

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is characterised by progressive cysts formation and renal enlargement that in most of cases leads to end stage of renal disease (ESRD). This pathology is caused by mutations of either PKD1 or PKD2 genes that encode for polycystin-1 (PC1) and polycystin-2 (PC2), respectively. These proteins function as receptor-channel complex able to regulate calcium homeostasis. PKD1/2 loss of function impairs different signalling pathways including cAMP and mTOR that are considered therapeutic targets for this disease. In fact, Tolvaptan, a vasopressin-2 antagonist that reduces cAMP levels, is the only drug approved for ADPKD treatment. Nevertheless, some ADPKD patients developed side effects in response to Tolvaptan including liver damage. Conversely, mTOR inhibitors that induced disease regression in ADPKD animal models failed the clinical trials.

Results

Here, we show that the inhibition of mTOR causes the activation of autophagy in ADPKD cells that could reduce therapy effectiveness by drug degradation through the autophagic vesicles. Consistently, the combined treatment with rapamycin and chloroquine, an autophagy inhibitor, potentiates the decrease of cell proliferation induced by rapamycin. To overcome the dangerous activation of autophagy by mTOR inhibition, we targeted MDM2 (a downstream effector of mTOR signalling) that is involved in TP53 degradation by using RG7112, a small-molecule MDM2 inhibitor used for the treatment of haematologic malignancies. The inhibition of MDM2 by RG7112 prevents TP53 degradation and increases p21 expression leading to the decrease of cell proliferation and the activation of apoptosis.

Conclusion

The targeting of MDM2 by RG7112 might represent a new therapeutic option for the treatment of ADPKD.

As the repository of genetic information, the cell nucleus must protect DNA integrity from mechanical stresses. The nuclear lamina, which resides within the nuclear envelope (NE), is made up of lamins, intermediate filaments bound to DNA. The nuclear lamina provides the nucleus with the ability to deal with inward as well as outward mechanical stimuli. Chromatin, in turn, through its degrees of compaction, shares this role with the nuclear lamina, thus, ensuring the plasticity of the nucleus. Perturbation of chromatin condensation or the nuclear lamina has been linked to a plethora of biological conditions, that range from cancer and genetic diseases (laminopathies) to aging, both natural and accelerated, such as the case of Hutchinson-Gilford Progeria Syndrome (HGPS). From the experimental results accumulated so far on the topic, a direct link between variations of the epigenetic pattern and nuclear lamina structure would be suggested, however, it has never been clarified thoroughly. This relationship, instead, has a downstream important implication on nucleus shape, genome preservation, force sensing, and, ultimately, aging-related disease onset. With this review, we aim to collect recent studies on the importance of both nuclear lamina components and chromatin status in nuclear mechanics. We also aim to bring to light evidence of the link between DNA methylation and nuclear lamina in natural and accelerated aging.

Background Information

Cilia and flagella are dynamic organelles whose assembly and maintenance depend on an activetrafficking process known as the IntraFlagellar Transport (IFT), during which trains of IFT protein particles are moved by specific motors and carry flagellar precursors and turnover products along the axoneme. IFT consists of an anterograde (from base to tip) and a retrograde (from tip to base) phase. During IFT turnaround at the flagellar tip, anterograde trains release their cargoes and remodel to form the retrograde trains. Thus, turnaround is crucial for correct IFT. However, current knowledge of its mechanisms is limited.

Results

We show here that in Chlamydomonas flagella the distal ∼200 nm central pair (CP) segment is structurally differentiated for the presence of a ladder-like structure (LLS). During IFT turnaround, the IFT172 subunit dissociates from the IFT- B protein complex and binds to the LLS-containing CP segment, while the IFT-B complex participates in the assembly of the CP capping structures. The IFT scaffolding function played by the LLS-containing CP segment relies on anchoring components other than the CP microtubules, since IFT turnaround occurs also in the CP-devoid pf18 mutant flagella.

Conclusions

During IFT turnaround in Chlamydomonas flagella, i) the LLS and the CP terminal plates act as anchoring platforms for IFT172 and the IFT-B complex, respectively, and ii) during its remodeling, the IFT-B complex contributes to the assembly of the CP capping structures.

Significance

Our results indicate that in full length Chlamydomonas flagella IFT remodeling occurs by a specialized mechanism that involves flagellar tip structures and is distinct from the previously proposed model in which the capability to reverse motility would be intrinsic of IFT train and independent by any other flagellar structure.

Background Information

Mitofusin2 (MFN2), an important molecular player that regulates mitochondrial fusion, also helps maintain the inter-organellar contact sites, referred as mitochondria associated membranes (MAMs) that exist between the ER and mitochondria. The study deals with a mutant of MFN2, R364W-MFN2, linked with the neuropathy, Charcot Marie Tooth (CMT) disease. Previous studies show that this mutant promotes mitochondrial hyperfusion. Here, we try to decipher the role of R364W-MFN2 in affecting the ER mitochondrial associations at the MAM junctions and inter-organellar calcium signalling between the ER and the mitochondria.

Results

Our results show that R364W-MFN2 altered ER-mitochondria association at the MAM junctions, predisposed mitochondria towards cellular stress with the mitochondria undergoing rapid fission upon induction of mild stress and perturbs inter-organellar calcium homeostasis.

Conclusion

The results indicate that R364W-MFN2 not only affects mitochondrial morphology and dynamics but also modulate its interaction with the ER and Ca²⁺ signalling between the two organelles.

Significance

This study provides significant insight that presence of the R364W-MFN2 mutation makes cells susceptible towards stress, thus negatively affecting cellular health which altogether might culminate in the form of the CMT neuropathy.