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:10.1101/2023.01.26.525799

Cited by 3 publications

(3 citation statements)

References 97 publications

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“…Previous studies in model organisms have shown that inhibition of mitochondrial function as well as components of the ETC and TCA cycle can extend lifespan in several species [36], including yeast [37], worms [38], flies [39], and mice [40]. For example, downregulation of aconitase and isocitrate dehydrogenase, two enzymes in the TCA cycle, leads to lifespan extension in worms [41].…”

Section: Discussionmentioning

confidence: 99%

Lifespan regulation by targeting heme signaling in yeast

Patnaik,

Nady,

Barlit

et al. 2024

Preprint

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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 significant lifespan extension in yeast. 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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Section: Discussionmentioning

confidence: 99%

Lifespan regulation by targeting heme signaling in yeast

Patnaik,

Nady,

Barlit

et al. 2024

Preprint

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show abstract

“…Similarly, studies have demonstrated that the plasticity of mitochondrial function could be a potential target to promote healthy aging [72,73]. 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 [74,75].…”

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

Preprint

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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 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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“…Limitations of the study Together, our results suggest the existence of a previously unanticipated role of heme in the regulation of lifespan in yeast and raise an exciting possibility that increased heme levels may extend lifespan in other organisms. Previous studies have shown that inhibition of mitochondrial function as well as components of the ETC and TCA cycle can extend the lifespan in several species [39], including yeast [40], worms [41], flies [42], and mice [43]. For example, the downregulation of aconitase and isocitrate dehydrogenase, two enzymes in the TCA cycle, leads to lifespan extension in worms [44].…”

Section: Discussionmentioning

confidence: 99%

Lifespan regulation by targeting heme signaling in yeast

Patnaik,

Nady,

Barlit

et al. 2024

GeroScience

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 3 publications

References 97 publications

Lifespan regulation by targeting heme signaling in yeast

Lifespan regulation by targeting heme signaling in yeast

Molecular Mechanisms of Genotype-Dependent Lifespan Variation Mediated by Caloric Restriction: Insight from Wild Yeast Isolates

Lifespan regulation by targeting heme signaling in yeast

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