<i>SNF1</i> controls the glycolytic flux and mitochondrial respiration

Martinez-Ortiz, Cecilia; Carrillo-Garmendia, Andres; Correa-Romero, Blanca Flor; Canizal-García, Melina; González‐Hernández, Juan Carlos; Regalado‐González, Carlos; Olivares-Marin, Ivanna Karina; Madrigal‐Perez, Luis Alberto

doi:10.1002/yea.3399

Cited by 15 publications

(10 citation statements)

References 33 publications

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“…It is important to note that the reductions observed in intracellular ATP levels in snf1∆ cells in the presence of glucose were overlooked in previous biochemical analyses, again demonstrating the usefulness of QUEEN-based ATP imaging. A recent study showed that the deletion of SNF1 decreased glycolytic flux in cells cultured in 1% glucose ( Martinez-Ortiz et al, 2019 ), which supports the novel function of the Snf1 complex.…”

Section: Discussionmentioning

confidence: 74%

High and stable ATP levels prevent aberrant intracellular protein aggregation in yeast

Takaine

Imamura

Yoshida

2022

eLife

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Adenosine triphosphate (ATP) at millimolar levels has recently been implicated in the solubilization of cellular proteins. However, the significance of this high ATP level under physiological conditions and the mechanisms that maintain ATP remain unclear. We herein demonstrated that AMP-activated protein kinase (AMPK) and adenylate kinase (ADK) cooperated to maintain cellular ATP levels regardless of glucose levels. Single-cell imaging of ATP-reduced yeast mutants revealed that ATP levels in these mutants underwent stochastic and transient depletion, which promoted the cytotoxic aggregation of endogenous proteins and pathogenic proteins, such as huntingtin and α-synuclein. Moreover, pharmacological elevations in ATP levels in an ATP-reduced mutant prevented the accumulation of α-synuclein aggregates and its cytotoxicity. The present study demonstrates that cellular ATP homeostasis ensures proteostasis and revealed that suppressing the high volatility of cellular ATP levels prevented cytotoxic protein aggregation, implying that AMPK and ADK are important factors that prevent proteinopathies, such as neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 74%

High and stable ATP levels prevent aberrant intracellular protein aggregation in yeast

Takaine

Imamura

Yoshida

2022

eLife

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“…In yeast, SNF1 controls glycolytic flux and mitochondrial respiration in a glucose-dependent manner. At 1% glucose, a concentration which we used in M2 medium in our studies with P. anserina, ScSNF1 sustains glycolytic flux and increases respiration (Martinez-Ortiz et al, 2019). Such a function of PaSNF1 in the PaClpP background appears to be not possible because, as revealed by the metabolome analysis, glycolytic flux seems to be impaired in the PaClpP deletion strain leading to the accumulation of C6 sugars and depletion of C3 carbohydrates and because complex I-and complex II-dependent respiration is impaired (Knuppertz and Osiewacz, 2017).…”

Section: Discussionmentioning

confidence: 99%

Simultaneous Ablation of the Catalytic AMPK α-Subunit SNF1 and Mitochondrial Matrix Protease CLPP Results in Pronounced Lifespan Extension

Heinz

Krotova

Hamann

et al. 2021

Front. Cell Dev. Biol.

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Organismic aging is known to be controlled by genetic and environmental traits. Pathways involved in the control of cellular metabolism play a crucial role. Previously, we identified a role of PaCLPP, a mitochondrial matrix protease, in the control of the mitochondrial energy metabolism, aging, and lifespan of the fungal aging model Podospora anserina. Most surprisingly, we made the counterintuitive observation that the ablation of this component of the mitochondrial quality control network leads to lifespan extension. In the current study, we investigated the role of energy metabolism of P. anserina. An age-dependent metabolome analysis of the wild type and a PaClpP deletion strain verified differences and changes of various metabolites in cultures of the PaClpP mutant and the wild type. Based on these data, we generated and analyzed a PaSnf1 deletion mutant and a ΔPaSnf1/ΔPaClpP double mutant. In both mutants PaSNF1, the catalytic α-subunit of AMP-activated protein kinase (AMPK) is ablated. PaSNF1 was found to be required for the development of fruiting bodies and ascospores and the progeny of sexual reproduction of this ascomycete and impact mitochondrial dynamics and autophagy. Most interestingly, while the single PaSnf1 deletion mutant is characterized by a slight lifespan increase, simultaneous deletion of PaSnf1 and PaClpP leads to a pronounced lifespan extension. This synergistic effect is strongly reinforced in the presence of the mating-type “minus”-linked allele of the rmp1 gene. Compared to the wild type, culture temperature of 35°C instead of the standard laboratory temperature of 27°C leads to a short-lived phenotype of the ΔPaSnf1/ΔPaClpP double mutant. Overall, our study provides novel evidence for complex interactions of different molecular pathways involved in mitochondrial quality control, gene expression, and energy metabolism in the control of organismic aging.

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“…We next sought to determine a mechanism by which NuA4 may regulate mitochondrial morphology and volume. We first focused our attention on the AMPK/Snf1 and PKA-Msn2/Msn4 axis as they have both been implicated in mitochondrial dynamics [32,[69][70][71][72]. Snf1 is a key kinase in yeast metabolic signalling [27].…”

Section: Mitochondrial Elongation In Eaf1δ Cells Can Be Partially Reversed Upon Deletion Of Bcy1mentioning

confidence: 99%

Phenomic screen identifies a role for the yeast lysine acetyltransferase NuA4 in the control of Bcy1 subcellular localization, glycogen biosynthesis, and mitochondrial morphology

et al. 2020

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Cellular metabolism is tightly regulated by many signaling pathways and processes, including lysine acetylation of proteins. While lysine acetylation of metabolic enzymes can directly influence enzyme activity, there is growing evidence that lysine acetylation can also impact protein localization. As the Saccharomyces cerevisiae lysine acetyltransferase complex NuA4 has been implicated in a variety of metabolic processes, we have explored whether NuA4 controls the localization and/or protein levels of metabolic proteins. We performed a high-throughput microscopy screen of over 360 GFP-tagged metabolic proteins and identified 23 proteins whose localization and/or abundance changed upon deletion of the NuA4 scaffolding subunit, EAF1. Within this, three proteins were required for glycogen synthesis and 14 proteins were associated with the mitochondria. We determined that in eaf1Δ cells the transcription of glycogen biosynthesis genes is upregulated resulting in increased proteins and glycogen production. Further, in the absence of EAF1, mitochondria are highly fused, increasing in volume approximately 3-fold, and are chaotically distributed but remain functional. Both the increased glycogen synthesis and mitochondrial elongation in eaf1Δ cells are dependent on Bcy1, the yeast regulatory subunit of PKA. Surprisingly, in the absence of EAF1, Bcy1 localization changes from being nuclear to cytoplasmic and PKA activity is altered. We found that NuA4-dependent localization of Bcy1 is dependent on a lysine residue at position 313 of Bcy1. However, the glycogen accumulation and mitochondrial elongation phenotypes of eaf1Δ, while dependent on Bcy1, were not fully dependent on Bcy1-K313 acetylation state and subcellular localization of Bcy1. As NuA4 is highly conserved with the human Tip60 complex, our work may inform human disease biology, revealing new avenues to investigate the role of Tip60 in metabolic diseases.

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SNF1 controls the glycolytic flux and mitochondrial respiration

Cited by 15 publications

References 33 publications

High and stable ATP levels prevent aberrant intracellular protein aggregation in yeast

High and stable ATP levels prevent aberrant intracellular protein aggregation in yeast

Simultaneous Ablation of the Catalytic AMPK α-Subunit SNF1 and Mitochondrial Matrix Protease CLPP Results in Pronounced Lifespan Extension

Phenomic screen identifies a role for the yeast lysine acetyltransferase NuA4 in the control of Bcy1 subcellular localization, glycogen biosynthesis, and mitochondrial morphology

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