Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan

Phua, Clifton; Zhao, Xiaqing; Turcios-Hernandez, Lesly; McKernan, Morrigan; Abyadeh, Morteza; Ma, Siming; Promislow, Daniel; Kaeberlein, Matt; Kaya, Alaattin

doi:10.1007/s11357-023-00796-4

Cited by 6 publications

(1 citation statement)

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“…Similarly, studies have demonstrated that the plasticity of mitochondrial function could be a potential target to promote healthy aging ( Lima et al, 2022 ; Phua et al, 2023 ). Mitochondria have an important role in a wide variety of metabolic and cellular processes, including energy production, amino acid synthesis, lipid metabolism, cell cycle regulation, apoptosis, autophagy, and signaling processes, and many of these processes are directly linked to lifespan regulation and aging ( Goodell and Rando, 2015 ; Jang et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of genotype-dependent lifespan variation mediated by caloric restriction: insight from wild yeast isolates

McLean,

Lee,

Liu

et al. 2024

Front. Aging

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Caloric restriction (CR) is known to extend lifespan across different species and holds great promise for preventing human age-onset pathologies. However, two major challenges exist. First, despite extensive research, the mechanisms of lifespan extension in response to CR remain elusive. Second, genetic differences causing variations in response to CR and genetic factors contributing to variability of CR response on lifespan are largely unknown. Here, we took advantage of natural genetic variation across 46 diploid wild yeast isolates of Saccharomyces species and the lifespan variation under CR conditions to uncover the molecular factors associated with CR response types. We identified genes and metabolic pathways differentially regulated in CR-responsive versus non-responsive strains. Our analysis revealed that altered mitochondrial function and activation of GCN4-mediated environmental stress response are inevitably linked to lifespan variation in response to CR and a unique mitochondrial metabolite might be utilized as a predictive marker for CR response rate. In sum, our data suggests that the effects of CR on longevity may not be universal, even among the closely related species or strains of a single species. Since mitochondrial-mediated signaling pathways are evolutionarily conserved, the dissection of related genetic pathways will be relevant to understanding the mechanism by which CR elicits its longevity effect.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of genotype-dependent lifespan variation mediated by caloric restriction: insight from wild yeast isolates

McLean,

Lee,

Liu

et al. 2024

Front. Aging

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Lifespan regulation by targeting heme signaling in yeast

Patnaik,

Nady,

Barlit

et al. 2024

GeroScience

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Heme is an essential prosthetic group that serves as a co-factor and a signaling molecule. Heme levels decline with age, and its deficiency is associated with multiple hallmarks of aging, including anemia, mitochondrial dysfunction, and oxidative stress. Dysregulation of heme homeostasis has been also implicated in aging in model organisms suggesting that heme may play an evolutionarily conserved role in controlling lifespan. However, the underlying mechanisms and whether heme homeostasis can be targeted to promote healthy aging remain unclear. Here, we used Saccharomyces cerevisiae as a model to investigate the role of heme in aging. For this, we have engineered a heme auxotrophic yeast strain expressing a plasma membrane-bound heme permease from Caenorhabditis elegans (ceHRG-4). This system can be used to control intracellular heme levels independently of the biosynthetic enzymes by manipulating heme concentration in the media. We observed that heme supplementation leads to a significant extension of yeast replicative lifespan. Our findings revealed that the effect of heme on lifespan is independent of the Hap4 transcription factor. Surprisingly, heme-supplemented cells had impaired growth on YPG medium, which requires mitochondrial respiration to be used, suggesting that these cells are respiratory deficient. Together, our results demonstrate that heme homeostasis is fundamentally important for aging biology, and manipulating heme levels can be used as a promising therapeutic target for promoting longevity.

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The Promising Role of Selenium and Yeast in the Fight Against Protein Amyloidosis

Kieliszek,

Sapazhenkava

2024

Biol Trace Elem Res

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In recent years, increasing attention has been paid to research on diseases related to the deposition of misfolded proteins (amyloids) in various organs. Moreover, modern scientists emphasise the importance of selenium as a bioelement necessary for the proper functioning of living organisms. The inorganic form of selenium—sodium selenite (redox-active)—can prevent the formation of an insoluble polymer in proteins. It is very important to undertake tasks aimed at understanding the mechanisms of action of this element in inhibiting the formation of various types of amyloid. Furthermore, yeast cells play an important role in this matter as a eukaryotic model organism, which is intensively used in molecular research on protein amyloidosis. Due to the lack of appropriate treatment in the general population, the problem of amyloidosis remains unsolved. This extracellular accumulation of amyloid is one of the main factors responsible for the occurrence of Alzheimer’s disease. The review presented here contains scientific information discussing a brief description of the possibility of amyloid formation in cells and the use of selenium as a factor preventing the formation of these protein aggregates. Recent studies have shown that the yeast model can be successfully used as a eukaryotic organism in biotechnological research aimed at understanding the essence of the entire amyloidosis process. Understanding the mechanisms that regulate the reaction of yeast to selenium and the phenomenon of amyloidosis is important in the aetiology and pathogenesis of various disease states. Therefore, it is imperative to conduct further research and analysis aimed at explaining and confirming the role of selenium in the processes of protein misfolding disorders. The rest of the article discusses the characteristics of food protein amyloidosis and their use in the food industry. During such tests, their toxicity is checked because not all food proteins can produce amyloid that is toxic to cells. It should also be noted that a moderate diet is beneficial for the corresponding disease relief caused by amyloidosis.

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Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan

Cited by 6 publications

References 100 publications

Molecular mechanisms of genotype-dependent lifespan variation mediated by caloric restriction: insight from wild yeast isolates

Molecular mechanisms of genotype-dependent lifespan variation mediated by caloric restriction: insight from wild yeast isolates

Lifespan regulation by targeting heme signaling in yeast

The Promising Role of Selenium and Yeast in the Fight Against Protein Amyloidosis

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