Loss of Cotl1 disrupts mitochondrial fission and impairs learning and memory in mice

Mitochondrial morphology dynamics are essential for neuronal function and are regulated by fission and fusion machinery, in which the actin cytoskeleton plays a crucial role. Coactosin-like F-actin-binding protein 1 (Cotl1), a key component of the actin cytoskeleton, is gaining attention for its profound pathophysiological implications in human neurodegenerative disorders. However, its role in neuronal function remains unclear. Therefore, we aimed to explore the role of Cotl1 in mitochondrial morphology and neuronal dysfunction. We generated Cotl1-knockdown and Cotl1-K75E mutants to examine mitochondrial structure and produced Cotl1-knockout (Cotl1^-/-) mice to assess learning and memory-related phenotypes. Both Cotl1 knockdown and Cotl1-K75E overexpression induced mitochondrial elongation and disrupted F-actin organization by inhibiting fission. In silico analysis of differentially expressed genes in Cotl1^-/- hippocampal tissue revealed a link between Cotl1 and neuronal function. Cotl1^-/- mice further exhibited impaired learning and memory, accompanied by decreased doublecortin (Dcx) expression in the hippocampal dentate gyrus (DG). Notably, restoration of Cotl1 expression in the DG recovered both Dcx expression and cognitive functions. These results highlight the crucial role of Cotl1 in mitochondrial fission through its regulation of F-actin and Drp1 assembly in the mitochondria, and they link Cotl1 loss to impaired learning and memory and to reduced Dcx expression in the hippocampal DG. Collectively, these findings suggest an important role of Cotl1 in maintaining developing granule neurons in the dentate gyrus, a process closely linked to mitochondrial fission and cognitive function.