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CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression

ABSTRACT: Proliferating cells undergo metabolic changes in synchrony with cell cycle progression and cell division. Mitochondria provide fuel, metabolites, and ATP during different phases of the cell cycle, however it is not completely understood how mitochondrial function and the cell cycle are coordinated. CLUH is a post-transcriptional regulator of mRNAs encoding mitochondrial proteins involved in oxidative phosphorylation and several metabolic pathways. Here, we show a role of CLUH in regulating the expression of astrin, which is involved in metaphase to anaphase progression, centrosome integrity, and mTORC1 inhibition. We find that CLUH binds both the SPAG5 mRNA and its product astrin, and controls the synthesis and the stability of the full-length astrin-1 isoform. We show that CLUH interacts with astrin-1 specifically during interphase. Astrin-depleted cells show mislocalized CLUH at focal adhesions, mTORC1 hyperactivation and enhanced anabolism. On the other hand, cells lacking CLUH show decreased astrin levels and increased mTORC1 signaling, but cannot sustain anaplerotic and anabolic pathways. In absence of CLUH, cells fail to grow during G1, and progress faster through the cell cycle, indicating dysregulated matching of growth, metabolism and cell cycling. Our data reveal a role of CLUH in coupling growth signaling pathways and mitochondrial metabolism with cell cycle progression.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Prerana Wagle

LAB HEAD: Elena I. Rugarli

PROVIDER: PXD029145 | Pride | 2022-05-30

REPOSITORIES: Pride

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			Action	DRS
	HUMANc_UP000005640_Proj2584.fasta	Fasta
	Q1_ColID_230_2584_01.raw	Raw
	Q1_ColID_230_2584_03.raw	Raw
	Q1_ColID_230_2584_07.raw	Raw
	Q1_ColID_230_2584_09.raw	Raw

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CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression

Project description:Proliferating cells undergo metabolic changes in synchrony with cell cycle progression and cell division. Mitochondria provide fuel, metabolites, and ATP during different phases of the cell cycle, however it is not completely understood how mitochondrial function and the cell cycle are coordinated. CLUH is a post-transcriptional regulator of mRNAs encoding mitochondrial proteins involved in oxidative phosphorylation and several metabolic pathways. Here, we show a role of CLUH in regulating the expression of astrin, which is involved in metaphase to anaphase progression, centrosome integrity, and mTORC1 inhibition. We find that CLUH binds both the SPAG5 mRNA and its product astrin, and controls the synthesis and the stability of the full-length astrin-1 isoform. We show that CLUH interacts with astrin-1 specifically during interphase. Astrin-depleted cells show mislocalized CLUH at focal adhesions, mTORC1 hyperactivation and enhanced anabolism. On the other hand, cells lacking CLUH show decreased astrin levels and increased mTORC1 signaling, but cannot sustain anaplerotic and anabolic pathways. In absence of CLUH, cells fail to grow during G1, and progress faster through the cell cycle, indicating dysregulated matching of growth, metabolism and cell cycling. Our data reveal a role of CLUH in coupling growth signaling pathways and mitochondrial metabolism with cell cycle progression.

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CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression

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CLUH-dependent RNA granules coordinate mitochondrial catabolic pathways with mTORC1 signaling and mitophagy

Project description:Mitochondria house anabolic and catabolic processes that must be balanced and rapidly adjusted to meet the cellular demands. CLUH binds mRNAs of nuclear encoded mitochondrial proteins and is highly expressed in the liver, where it regulates metabolic plasticity by an ill-defined mechanism. Here, we show that CLUH-dependent regulation of mitochondrial function is spatially organized through the coalescence of CLUH and its target mRNAs in specific G3BP1-positive granules. These CLUH-dependent granules protect mRNAs involved in mitochondrial energy-converting pathways from decay and define their translational fate to match nutrient availability. CLUH granules suppress premature mTORC1 activation during nutrient deprivation, inhibiting mitochondrial anabolic pathways. Lack of spatial CLUH regulation causes mTORC1 hyperactivation, which impairs mitophagy and triggers cell death. Our data demonstrate that the temporal catabolic adaptation of mitochondria depends on a compartmentalized CLUH-dependent post-transcriptional mechanism that controls mTORC1 signaling and mitochondrial turnover, thus ensuring survival.

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