Language
English
Publication Date
7-15-2024
Journal
Journal of Cell Science
DOI
10.1242/jcs.261268
PMID
38896010
PMCID
PMC11304411
PubMedCentral® Posted Date
7-26-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Mitochondria, which act as sensors of metabolic homeostasis and metabolite signaling, form a dynamic intracellular network that continuously changes shape, size and localization to respond to localized cellular energy demands. Mitochondrial dynamics and function depend on interactions with the F-actin cytoskeleton that are poorly understood. Here, we show that SET domain protein 3 (SETD3), a recently described actin histidine methyltransferase, directly methylates actin at histidine-73 and enhances F-actin polymerization on mitochondria. SETD3 is a mechano-sensitive enzyme that is localized on the outer mitochondrial membrane and promotes actin polymerization around mitochondria. SETD3 loss of function leads to diminished F-actin around mitochondria and a decrease in mitochondrial branch length, branch number and mitochondrial movement. Our functional analysis revealed that SETD3 is required for oxidative phosphorylation, and mitochondrial complex I assembly and function. Our data further indicate that SETD3 regulates F-actin formation around mitochondria and is essential for maintaining mitochondrial morphology, movement and function. Finally, we discovered that SETD3 levels are regulated by extracellular matrix (ECM) stiffness and regulate mitochondrial shape in response to changes in ECM stiffness. These findings provide new insight into the mechanism for F-actin polymerization around mitochondria.
Keywords
Actins, Humans, Mitochondria, Mitochondrial Dynamics, Methylation, Histidine, Extracellular Matrix, Methyltransferases, Animals, HeLa Cells, Histone Methyltransferases, Mitochondrial dynamics, Cytoskeleton, Mechanotransduction, Post-translational modifications
Published Open-Access
yes
Recommended Citation
Vaibhav Deshmukh and James F Martin, "SETD3 Is a Mechanosensitive Enzyme That Methylates Actin on His73 To Regulate Mitochondrial Dynamics and Function" (2024). Faculty and Staff Publications. 3989.
https://digitalcommons.library.tmc.edu/baylor_docs/3989