Anisotropic Micro/Nanotopography Regulating Mitochondrial Dynamics in Cardiomyocytes.

Topographical cues of biomaterial scaffolds directly guide cell behaviors by determining integrin ligation and subsequent mechanotransducive pathways, but their influence on organelle (e.g., mitochondrion) behaviors remains unclear. Considering the high sensitivity of mitochondria in cardiomyocytes to topographical signals, this study focused on investigating the impact of oriented micro/nano-wrinkled surfaces with varying wavelengths (0.5 to 25.0 μm) and amplitudes (0.05 to 4.30 μm) on the mitochondrial functions of rat embryonic myocardial cell line H9c2. The results uncover a nonlinear response of cardiomyocyte behavior and mitochondrial homeostasis to these surface features. Notably, surfaces with a 3-μm wavelength and 0.7-μm amplitude (W3) promoted substantial cell elongation and orientation, whereas surfaces with a 0.5-μm wavelength and 0.05-μm amplitude (W0.5) triggered pronounced mitochondrial division. Remarkably, W0.5 topography facilitated mitochondrial division via cytoskeletal remodeling, involving vinculin and tubulin, which disrupted mitochondrial energy metabolism, enhanced reactive oxygen species (ROS)-mediated oxidative stress, and perturbed mitochondrial homeostasis by stimulating the adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway. The transcriptomic analysis identifies the pivotal involvement of the p53, FoxO, mTOR, HIF-1, and AMPK signaling pathways in regulating mitochondrial dynamics in myocardial cells induced by W0.5, confirming the essential role of the polyadenylation signal (AATAAA) in modulating transcript splicing processes. Overall, this study offers important insights into the regulatory mechanisms by which aligned micro/nano topographical stimuli impact mitochondrial responses in cardiomyocytes, which hold potential for the development of novel biomaterial-focused approaches for diagnosing and treating cardiovascular diseases.