title: Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics.
abstract: Aberrant mitochondrial function, morphology, and transport are main features of neurodegenerative diseases. To date, mitochondrial transport within neurons is thought to rely mainly on microtubules, whereas actin might mediate short-range movements and mitochondrial anchoring. Here, we analyzed the impact of actin on neuronal mitochondrial size and localization. F-actin enhanced mitochondrial size and mitochondrial number in neurites and growth cones. In contrast, raising G-actin resulted in mitochondrial fragmentation and decreased mitochondrial abundance. Cellular F-actin/G-actin levels also regulate serum response factor (SRF)-mediated gene regulation, suggesting a possible link between SRF and mitochondrial dynamics. Indeed, SRF-deficient neurons display neurodegenerative hallmarks of mitochondria, including disrupted morphology, fragmentation, and impaired mitochondrial motility, as well as ATP energy metabolism. Conversely, constitutively active SRF-VP16 induced formation of mitochondrial networks and rescued huntingtin (HTT)-impaired mitochondrial dynamics. Finally, SRF and actin dynamics are connected via the actin severing protein cofilin and its slingshot phosphatase to modulate neuronal mitochondrial dynamics. In summary, our data suggest that the SRF-cofilin-actin signaling axis modulates neuronal mitochondrial function.
authors.affiliation: Graduate School of Cellular and Molecular Neuroscience,  University of Tübingen, 72076 Tübingen,  Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Beck
authors.forename: Kevin
authors.initials: K
authors.lastname: Flynn
authors.forename: Katrin S
authors.initials: KS
authors.lastname: Lindenberg
authors.forename: Heinz
authors.initials: H
authors.lastname: Schwarz
authors.forename: Frank
authors.initials: F
authors.lastname: Bradke
authors.forename: Simone
authors.initials: S
authors.lastname: Di Giovanni
authors.forename: Bernd
authors.initials: B
authors.lastname: Knöll
mesh_terms: D000199:Actins / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D051338:Cofilin 1 / Q000378:metabolism*; D017405:Herpes Simplex Virus Protein Vmw65 / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D000071058:Huntingtin Protein; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction; D014018:Tissue Distribution
chemical_list: D000199:Actins; D051338:Cofilin 1; D017405:Herpes Simplex Virus Protein Vmw65; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D026362:Serum Response Factor; D000255:Adenosine Triphosphate; D010744:Phosphoric Monoester Hydrolases