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β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial quality control

ABSTRACT: Mitochondrial dynamics and metabolites reciprocally influence each other. Mitochondrial-derived vesicles (MDVs) transport damaged mitochondrial components to lysosomes or the extracellular space, and they are an emerging mechanism that regulates mitochondrial quality. While many metabolites are known to modulate mitochondrial dynamics, it is largely unclear whether they are involved in MDVs generation. Here, we discovered that the major component of ketone body, β-hydroxybutyrate (BHB), improved mitochondrial quality control by facilitating the biogenesis of MDVs. Mechanistically, BHB supplementation drove lysine β-hydroxybutyrylation (Kbhb) of SNX9, a key regulator of MDV biogenesis, at three specific lysine residues. Kbhb increased SNX9 interaction with inner mitochondrial membrane (IMM)/matrix proteins and promoted the formation of IMM/matrix MDVs. Lastly, we found that SNX9 Kbhb not only played a critical role in maintaining mitochondrial homeostasis in cells, but also protected mice from alcohol-induced liver injury. Altogether, our research uncovers that metabolites influence the formation of MDVs by directly engaging in post-translational modifications of key protein machineries and establishes a new framework for understanding how metabolites regulate mitochondrial quality

ORGANISM(S): Homo Sapiens

SUBMITTER: Lunzhi Dai

PROVIDER: PXD045541 | iProX | Thu Sep 21 00:00:00 BST 2023

REPOSITORIES: iProX

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