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Mitochondrial Ca2+ homeostasis controls inter-compartmental proteostasis in Arabidopsis plants [Ribo-seq]

ABSTRACT: Purpose: The goals of this study are to determine the effects of mitochondrial Ca2+ homeostasis on cytosolic translation Methods: The monosomal and polysomal mRNA profiles of 10-day-old WT, MCU2 overexpression and mcu sextuple mutation plants were generated by deep sequencing, in triplicate, using Illumina HiSeq2500. The sequence reads that passed quality filters were analyzed at the transcript isoform level with TopHat followed by Cufflinks Results: Using an optimized data analysis workflow, we mapped a minimum of 23 million sequence reads per sample to the Arabidopsis genome (TAIR10) and identified more than 23,000 transcripts. Data analysis revealed that perturbation of mitochondrial Ca2+ altered specifically the translational efficiency of RNA modification genes Conclusions: Our study represents the first detailed analysis of Arabidopsis monosomal and polysomal RNA transcriptomes in response to impaired mitochondrial Ca2+, with biologic replicates, generated by RNA-seq technology. Our results showed that perturbation of mitochondrial Ca2+ triggered cytosolic translation response. We conclude that RNA-seq based transcriptome characterization would expedite genetic network analyses of inter-compartmental communication

ORGANISM(S): Arabidopsis thaliana

PROVIDER: GSE186417 | GEO | 2026/06/03

REPOSITORIES: GEO

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Project description:Chronic low-grade inflammation is a hallmark of aging, but its etiology is not well understood. Mitochondrial dysfunction has been linked to both cellular senescence and age-related inflammation or inflammaging but fundamental mechanisms underlying these links are unclear. We analyzed age-related gene expression in different human tissues and discovered that in blood, the mRNA expression of Mitochondrial Calcium Uniporter (MCU) and its regulatory subunit MICU1 correlated inversely with age. MCU is the pore-forming subunit of a Ca2+-selective ion channel complex residing in the mitochondrial inner membrane and is the main conduit for Ca2+-influx into the mitochondrial matrix. Based on these findings we tested the simple hypothesis that mitochondrial Ca2+ uptake capacity of macrophages decreases with age. We found a significant reduction in the mitochondrial Ca2+-uptake capacity of macrophages derived from aged (80-90 weeks) mice. Notably, these macrophages display amplified cytosolic Ca2+ elevations and increased inflammatory output. To test the salience of mitochondrial calcium uptake in regulating macrophage inflammatory output, we deleted Mcu selectively in macrophages. The Mcu-/- macrophages of young mice (<25 weeks) express more inflammatory genes at baseline and show a hyper-inflammatory response when stimulated. We show that reduced mitochondrial Ca2+ amplifies cytosolic Ca2+ oscillations and potentiates downstream NFkB activation, which is central to inflammation. The regulation of inflammatory response by mitochondrial Ca2+ uptake is also seen readily in human macrophages. The siRNA-mediated knockdown of MCU in human blood derived macrophages recapitulates the phenomenon – the mitochondrial Ca2+-uptake is greatly reduced, cytosolic Ca2+ elevations are more pronounced, and the macrophages are hyper-inflammatory. Our findings pinpoint the MCU complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to macrophage-mediated inflammation. Resident macrophages are intrinsic to every organ system and the steady erosion of their mitochondrial Ca2+-uptake capacity may play a germinal or exacerbating role in many age-related neurodegenerative, cardiometabolic, renal and musculoskeletal diseases that afflict us.

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Mitochondrial Ca2+ homeostasis controls inter-compartmental proteostasis in Arabidopsis plants [Ribo-seq]

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