The Landscape of Subcellular Long Non-coding RNAs Links Organelle Metabolic Homeostasis

Abstract Organelles entail specialized molecules to regulate their essential cellular processes. However, systematically elucidating the subcellular distribution of functional molecules such as long non-coding RNAs (lncRNAs) in tissue homeostasis and diseases has not been fully achieved. Here, we characterized the organelle-associated lncRNAs from mitochondria, lysosome, and endoplasmic reticulum (ER), respectively, and revealed the diverse and abundant distribution of lncRNAs. Among them, we identified mitochondrial lncRNA Growth-Arrest-Specific 5 (GAS5) as a tumor suppressor in maintaining cellular energy homeostasis. Mechanistically, energy stress-induced GAS5 modulated mitochondria TCA flux by declining metabolic tandem association of FH-MDH2-CS, the canonical members of the TCA cycle. Remarkably, the expression of GAS5 negatively related with levels of its associated mitochondrial metabolic enzymes and breast cancer development. Together with the detailed functional annotations, this subcellular lncRNA identification revealed the human cell’s inquisitively complex architecture, aiding in the development of new strategies for the clinical application of organelle-associated lncRNAs.