The coordination of cytoskeletal proteins shapes cell architectures and functions. Age-related changes in cellular mechanical properties have been linked to decreased cellular and tissue dysfunction. Studies have also found a relationship between mitochondrial function and the cytoskeleton. Cytoskeleton inhibitors impact mitochondrial quality and function, including motility and morphology, membrane potential, and respiration. The regulatory properties of the cytoskeleton on mitochondrial functions are involved in the pathogenesis of several diseases. Disassembly of the axon's cytoskeleton and the release of neurofilament fragments have been documented during neurodegeneration. However, these changes can also be related to mitochondrial impairments, spanning from reduced mitochondrial quality to altered bioenergetics. Herein, we discuss recent research highlighting some of the pathophysiological roles of cytoskeleton disassembly in aging, neurodegeneration, and neuromuscular diseases, with a focus on studies that explored the relationship between intermediate filaments and mitochondrial signaling as relevant contributors to cellular health and disease.