Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging.

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), MTZ, a newly employed ETC complex I inhibitor, exhibited higher cytotoxicity against cancer cell lines compared to certain non-cancer cell lines. Interestingly, 8-OAc demonstrated greater selectivity for cancer cells when compared to both MTZ and Rote, which has promising potential for anticancer therapeutic development. Furthermore, in vivo experiments with these small molecules utilizing a C. elegans model demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. We also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilizes the transcription factors ATFS-1 and HSF1, which are involved in the UPRMT and heat shock response (HSR) pathways respectively, 8-OAc only required HSF1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging.

Transcript errors generate amyloid-like proteins in huwman cells.

Aging is characterized by the accumulation of proteins that display amyloid-like behavior. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that amyloid-like proteins are produced in a variety of human cell types, including stem cells, brain organoids and fully differentiated neurons by mistakes that occur in messenger RNA molecules. Some of these mistakes generate mutant proteins already known to cause disease, while others generate proteins that have not been observed before. Moreover, we show that these mistakes increase when cells are exposed to DNA damage, a major hallmark of human aging. When taken together, these experiments suggest a mechanistic link between the normal aging process and age-related diseases.

The intestinal immune system and gut barrier function in obesity and ageing.

Obesity and ageing predispose to numerous, yet overlapping chronic diseases. For example, metabolic abnormalities, including insulin resistance (IR) and type 2 diabetes (T2D) are important causes of morbidity and mortality. Low-grade chronic inflammation of tissues, such as the liver, visceral adipose tissue and neurological tissues, is considered a significant contributor to these chronic diseases. Thus, it is becoming increasingly important to understand what drives this inflammation in affected tissues. Recent evidence, especially in the context of obesity, suggests that the intestine plays an important role as the gatekeeper of inflammatory stimuli that ultimately fuels low-grade chronic tissue inflammation. In addition to metabolic diseases, abnormalities in the intestinal mucosal barrier have been linked to a range of other chronic inflammatory conditions, such as neurodegeneration and ageing. The flow of inflammatory stimuli from the gut is in part controlled by local immunological inputs impacting the intestinal barrier. Here, we will review the impact of obesity and ageing on the intestinal immune system and its downstream consequences on gut barrier function, which is strongly implicated in the pathogenesis of obesity and age-related diseases. In particular, we will discuss the effects of age-related intestinal dysfunction on neurodegenerative diseases.

Evolutionary conservation of the fidelity of transcription.

Accurate transcription is required for the faithful expression of genetic information. However, relatively little is known about the molecular mechanisms that control the fidelity of transcription, or the conservation of these mechanisms across the tree of life. To address these issues, we measured the error rate of transcription in five organisms of increasing complexity and found that the error rate of RNA polymerase II ranges from 2.9 × 10-6 ± 1.9 × 10-7/bp in yeast to 4.0 × 10-6 ± 5.2 × 10-7/bp in worms, 5.69 × 10-6 ± 8.2 × 10-7/bp in flies, 4.9 × 10-6 ± 3.6 × 10-7/bp in mouse cells and 4.7 × 10-6 ± 9.9 × 10-8/bp in human cells. These error rates were modified by various factors including aging, mutagen treatment and gene modifications. For example, the deletion or modification of several related genes increased the error rate substantially in both yeast and human cells. This research highlights the evolutionary conservation of factors that control the fidelity of transcription. Additionally, these experiments provide a reasonable estimate of the error rate of transcription in human cells and identify disease alleles in a subunit of RNA polymerase II that display error-prone transcription. Finally, we provide evidence suggesting that the error rate and spectrum of transcription co-evolved with our genetic code.

Investigating impacts of marine sponge derived mycothiazole and its acetylated derivative on mitochondrial function and aging.

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), a widely used ETC complex I inhibitor, these two molecules showed cytotoxicity to cancer cells but strikingly demonstrate a lack of toxicity to non-cancer cells, a highly beneficial feature in the development of anti-cancer therapeutics. Furthermore, in vivo experiments with these small molecules utilizing C.elegans model demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. Interestingly, we also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilize the transcription factors ATFS-1 and HSF-1, which are involved in the UPRMT and heat shock response (HSR) pathways respectively, 8-OAc only required HSF-1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging.