Journal Article

Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces

Aragona, Mariaceleste, Martello, Graziano, Arboit, Mattia, Rouni, Georgia, Benedetti, Giada, Cusan, Martina, Giampietro, Costanza, Wu, Xi, Grumati, Paolo, Romani, Patrizia, Dupont, Sirio, Cirillo, Carmine, Kostourou, Vassiliki

2024

Overview

Tissue-scale architecture and mechanical properties instruct cell behaviour under physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that extracellular matrix stiffness, spatial confinements and applied forces, including stretching of mouse skin, regulate mitochondrial dynamics. Actomyosin tension promotes the phosphorylation of mitochondrial elongation factor 1 (MIEF1), limiting the recruitment of dynamin-related protein 1 (DRP1) at mitochondria, as well as peri-mitochondrial F-actin formation and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed, we found that DRP1- and MIEF1/2-dependent fission is required and sufficient to regulate three transcription factors of broad relevance-YAP/TAZ, SREBP1/2 and NRF2-to control cell proliferation, lipogenesis, antioxidant metabolism, chemotherapy resistance and adipocyte differentiation in response to mechanical cues. This extends to the mouse liver, where DRP1 regulates hepatocyte proliferation and identity-hallmark YAP-dependent phenotypes. We propose that mitochondria fulfil a unifying signalling function by which the mechanical tissue microenvironment coordinates complementary cell functions.

• Publisher: Nature Publishing Group UK
• Subject: Actins - metabolism / Actomyosin - metabolism / Animals / Cell Nucleus - metabolism / Cell Proliferation / Dynamins - genetics / Dynamins - metabolism / Extracellular Matrix - metabolism / Hepatocytes - metabolism / Humans / Liver - metabolism / Male / Mechanotransduction, Cellular / Mice / Mice, Inbred C57BL / Mice, Knockout / Mitochondria - metabolism / Mitochondrial Dynamics / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - metabolism / Peptide Elongation Factors - genetics / Peptide Elongation Factors - metabolism / Phosphorylation / Transcription Factors - genetics / Transcription Factors - metabolism / YAP-Signaling Proteins - genetics / YAP-Signaling Proteins - metabolism