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.

Mitochondrial translocation and interaction of cofilin and Drp1 are required for erucin-induced mitochondrial fission and apoptosis

“…Recent evidence revealed that cofilin and Drp1 play critical roles in regulation of mitochondrial function by translocating from the cytosol to mitochondria [14, 17, 26–28]. We next investigated whether mitochondrial translocation of cofilin and Drp1 is necessary for erucin to induce mitochondrial fission.…”

“…Cofilin functions as a biosensor that integrates cytoskeletal regulation with mitochondrial function. The results of another study indicated that under certain cellular conditions cofilin might directly or indirectly associate with mitochondria and modulate mitochondrial functions [14]. However, the mechanism by which cofilin affects mitochondrial dynamics and functions, and is responsible for mitochondrial apoptosis remains unknown.…”

Novel roles for actin in mitochondrial fission

“…Because mammals contain homologs of each of these in the form of multiple genes and/or splice variants, it is possible that these factors are involved in mitochondrial fission. Indeed, there is some evidence that cofilin participates in mitochondrial dynamics in neurons (Beck et al, 2012).…”

Acrolein-induced inflammatory signaling in vascular smooth muscle cells requires activation of serum response factor (SRF) and NFκB

“…SRF, a member of the highly conserved MADS box family of transcription factors, has been shown to regulate several genes involved in cell growth [23] , migration [38] , cytoskeletal organization [39] , energy metabolism [40] and myogenesis [41] . The necessity of SRF for embryogenesis and early development has been reported [42] , whereas in adults low levels of SRF have been shown to be beneficial [43] .…”