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Endolysosomal protease leakage reprograms macrophage mitochondrial metabolism

ABSTRACT: Organelle crosstalk plays important functions in metabolic processes and is relevant to immunity, neurodegeneration, and cancer. The permeabilisation and rupture of endolysosomes during stress can induce inflammation and cell death. There is growing evidence that endomembrane damage does not always result in cell death and that important cellular functions can be regulated by limited endolysosomal damage. However, the effect of limited cytosolic leakage of endolysosomal contents on the function of other cytoplasmic organelles is poorly understood. Here, we show that sterile and non-sterile endolysosomal damage triggers remodelling of the mitochondrial proteome and metabolic reprogramming of human macrophages. Mitochondrial metabolic reprogramming was associated with endolysosomal leakage independently of proteasome degradation and mitophagy. Furthermore, single-cell RNA-sequencing and metabolic analysis of lung macrophages undergoing endomembrane damage showed altered mitochondrial metabolism in mice. We, therefore, uncover an inter-organelle communication mechanism between mitochondria and endolysosomes with limited proteolytic leakage, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprogramming in response to infection or injury.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Macrophage

SUBMITTER: Matthias Trost

LAB HEAD: Matthias Trost

PROVIDER: PXD026045 | Pride | 2022-10-30

REPOSITORIES: Pride

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			Action	DRS
	20201215_TH_CB_HA_BZIMB_01.raw	Raw
	20201215_TH_CB_HA_BZIMB_02.raw	Raw
	20201215_TH_CB_HA_BZIMB_03.raw	Raw
	20201215_TH_CB_HA_Ctrl_01.raw	Raw
	20201215_TH_CB_HA_Ctrl_02.raw	Raw

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Project description:One of the most common metabolic defects of cancer cells is the deficiency in arginine synthesis due to suppressed expression of argininosuccinate synthetase 1 (ASS1) which renders cancer cells auxotrophic to external arginine supply. Arginine deprivation has been effectively used as a treatment for leukemias, with several clinical trials on solid tumors underway. We previously showed that in prostate cancer arginine depletion induced mitochondrial dysfunction and excessive ROS production resulting in chromatin autophagy, nuclear DNA leakage, and cellular death, but the detailed mechanism of arginine starvation-induced cell death remains unclear. In this study, we demonstrated that arginine deprivation coordinately suppressed metabolic genes, including those responsible for mitochondrial oxidative phosphorylation (OXPHOS), nucleotide metabolism, and DNA repair. The consequent ROS production and impaired DNA damage response resulted in nuclear DNA leakage and cGAS-STING activation which is accompanied by upregulation of type I interferon response. We also showed that coordinated silencing of OXPHOS and DNA repair genes is caused in part by the depletion of α-ketoglutarate (αKG) and inactivation of histone demethylases. Supplementing cell-permeable dimethyl α-ketoglutarate (DMKG) both reduced repressive histone methylations and partially restored OXPHOS gene expressions, mitochondrial functions, and mitigated nuclear DNA leakage. Using our dietary arginine-restriction model, we demonstrate that arginine starvation slows prostate cancer growth with evidence of enhanced interferon responses and recruitment of immune cells. Our data suggests arginine starvation induces cell killing of ASS1-low cancer cells by metabolic depletion and epigenetic silencing of metabolic genes, leading to DNA damage and leakage. Resulting cGAS-STING activation may further enhance these killing effects. We used microarray to analyze the expression difference between control and arginine-depleted cells to find out what genes involved in the regulation of mitochondrial function and arginine deprivation-induced cell death.

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Endolysosomal protease leakage reprograms macrophage mitochondrial metabolism

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