bims-metalz 2023-09-17 papers

Issue of 2023–09–17
four papers selected by
Mikaila Chetty, Goa University

Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]

Mitochondrial degradation: Mitophagy and beyond.

Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.

Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.

Keywords: MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin

DOI: https://doi.org/10.1016/j.molcel.2023.08.021

Environ Geochem Health. 2023 Sep 12.

Effects of mixed heavy metals on obstructive lung function: findings from epidemiological and toxicogenomic data.

Hai Duc Nguyen.

The molecular mechanisms and associations of mixed heavy metals (lead, mercury, and cadmium) on obstructive lung function (OLF) in males and females remain unknown. Here, we evaluated the interaction between the forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio and three common heavy metals in males and females (n = 6221). Molecular processes involved in OLF development caused by mixed heavy metals were also identified to corroborate the earlier findings. In both males and females, as well as across the entire population, we found that serum cadmium levels were inversely related to the FEV1/FVC ratio. Interactions between serum cadmium and lead, as well as cadmium and mercury, were observed in relation to the FEV1/FVC ratio. Additionally, we observed negative correlations between the FEV1/FVC ratio and mixed serum cadmium, lead, and mercury in both men and women as well as in the overall population. Seven genes were identified as contributing to the etiology of OLF and targeted by combined heavy metals in silico analysis (CYP1A1, CRP, CXCL8, HMOX1, IL6, NOS2, and TNF). The primary relationships between these genes were co-expression interactions. The significant transcription factors and miRNAs associated with OLF and a combination of the examined heavy metals were identified as NFKB2, hsa-miR-155-5p, and hsa-miR-203a-3p. The main biological processes involved in the emergence of OLF induced by mixed heavy metals were listed as inflammatory and oxidative stress pathways, lung fibrosis, chronic obstructive pulmonary disease, as well as cytokine activity, monooxygenase activity, oxidoreductase activity, and interleukin-8 production. Threshold estimations and miRNA sponge patterns for heavy metal exposure levels associated with OLF were evaluated for both males and females. This study found that cadmium plays the most important role in the mixture of cadmium, lead, and mercury in the pathogenesis of OLF. Future studies are required to verify our findings and uncover the molecular mechanisms of long-term exposure to a variety of heavy metals, especially cadmium, in other populations, including children, adolescents, and the elderly.

Keywords: COPD; Heavy metals; Molecular mechanisms; Obstructive lung function

DOI: https://doi.org/10.1007/s10653-023-01746-x

Drug Dev Res. 2023 Sep 11.

Carbamate as a potential anti-Alzheimer's pharmacophore: A review.

Yash Pal Singh, Navneet Kumar, Brijesh Singh Chauhan, Prabha Garg.

Alzheimer's disease (AD) is a progressive age-related neurodegenerative brain disorder, which leads to loss of memory and other cognitive dysfunction. The underlying mechanisms of AD pathogenesis are very complex and still not fully explored. Cholinergic neuronal loss, accumulation of amyloid plaque, metal ions dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, and mitochondrial dysfunction are major hallmarks of AD. The current treatment options for AD are acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and NMDA receptor antagonists (memantine). These FDA-approved drugs mainly provide symptomatic relief without addressing the pathological aspects of disease progression. So, there is an urgent need for novel drug development that not only addresses the basic mechanisms of the disease but also shows the neuroprotective property. Various research groups across the globe are working on the development of multifunctional agents for AD amelioration using different core scaffolds for their design, and carbamate is among them. Rivastigmine was the first carbamate drug investigated for AD management. The carbamate fragment, a core scaffold of rivastigmine, act as a potential inhibitor of acetylcholinesterase. In this review, we summarize the last 10 years of research conducted on the modification of carbamate with different substituents which primarily target ChE inhibition, reduce oxidative stress, and modulate Aβ aggregation.

Keywords: Alzheimer's disease; carbamate; cholinesterase inhibitors

DOI: https://doi.org/10.1002/ddr.22113

Nat Rev Mol Cell Biol. 2023 Sep 14.

FOXO transcription factors as mediators of stress adaptation.

Maria J Rodriguez-Colman, Tobias B Dansen, Boudewijn M T Burgering.

The forkhead box protein O (FOXO, consisting of FOXO1, FOXO3, FOXO4 and FOXO6) transcription factors are the mammalian orthologues of Caenorhabditis elegans DAF-16, which gained notoriety for its capability to double lifespan in the absence of daf-2 (the gene encoding the worm insulin receptor homologue). Since then, research has provided many mechanistic details on FOXO regulation and FOXO activity. Furthermore, conditional knockout experiments have provided a wealth of data as to how FOXOs control development and homeostasis at the organ and organism levels. The lifespan-extending capabilities of DAF-16/FOXO are highly correlated with their ability to induce stress response pathways. Exogenous and endogenous stress, such as cellular redox stress, are considered the main drivers of the functional decline that characterizes ageing. Functional decline often manifests as disease, and decrease in FOXO activity indeed negatively impacts on major age-related diseases such as cancer and diabetes. In this context, the main function of FOXOs is considered to preserve cellular and organismal homeostasis, through regulation of stress response pathways. Paradoxically, the same FOXO-mediated responses can also aid the survival of dysfunctional cells once these eventually emerge. This general property to control stress responses may underlie the complex and less-evident roles of FOXOs in human lifespan as opposed to model organisms such as C. elegans.

DOI: https://doi.org/10.1038/s41580-023-00649-0