Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics

被引:45
作者
Beck, Henning [1 ,2 ,6 ,7 ]
Flynn, Kevin [3 ]
Lindenberg, Katrin S. [4 ]
Schwarz, Heinz [5 ]
Bradke, Frank [3 ]
Di Giovanni, Simone [2 ]
Knoell, Bernd [1 ,6 ]
机构
[1] Univ Ulm, Inst Physiol Chem, D-89081 Ulm, Germany
[2] Univ Tubingen, Hertie Inst Clin Brain Res, Lab NeuroRegenerat & Repair, Ctr Neurol, D-72076 Tubingen, Germany
[3] Deutsch Zentrum Neurodegenerat Erkrankungen, D-53175 Bonn, Germany
[4] Univ Ulm, Neurol Univ Clin, D-89081 Ulm, Germany
[5] Max Planck Inst Dev Biol, Microscopy Unit, D-72076 Tubingen, Germany
[6] Eberhard Karls Univ Tubingen, Interfac Inst Cell Biol, Dept Mol Biol, Neuronal Gene Express Lab, D-72076 Tubingen, Germany
[7] Univ Tubingen, Grad Sch Cellular & Mol Neurosci, D-72076 Tubingen, Germany
关键词
neurodegeneration; neuronal gene expression; NEURONAL MIGRATION; AXONAL-TRANSPORT; NEURODEGENERATIVE DISEASES; NEUROMUSCULAR-JUNCTION; TRANSCRIPTION FACTORS; HIPPOCAMPAL-NEURONS; HUNTINGTONS-DISEASE; GENE-TRANSCRIPTION; REGULATES COFILIN; TRANSGENIC MICE;
D O I
10.1073/pnas.1208141109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:E2523 / E2532
页数:10
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