MITOCHONDRIAL FISSION DYSFUNCTION DRIVES AGING-RELATED SYNAPTIC VULNERABILITY IN THE HIPPOCAMPUS

Aging is a major determinant of cognitive decline and a leading risk factor for neurodegenerative disorders. Defining the cellular mechanisms that initiate and propagate age-associated synaptic vulnerability is critical for identifying strategies to preserve cognitive function. Given the high energetic and redox demands of synapses, mitochondrial function is a key mediator of synaptic maintenance during aging. More specifically, mitochondrial dynamics, coordinated through fission/fusion, are essential for preserving brain homeostasis and synaptic integrity. This fission–fusion balance is disrupted in aging and neurodegenerative diseases. In the hippocampus, impaired mitochondrial fission is associated with neuronal vulnerability and impaired synaptic transmission and plasticity. However, it remains unclear whether mitochondrial fission dysfunction is an upstream driver that actively promotes aging-related synaptic deterioration.
Here, using a mitochondrial fission factor knockout (MFF KO) mouse model, we examined how mitochondrial fission affects age-related neural networks and synaptic integrity in the hippocampus. MFF KO showed reduced body and brain size and early mortality. Ultrastructural analyses in CA1 revealed mitochondrial remodeling, including giant mitochondria with unstable membranes, accompanied by reduced mitochondrial function. We further observed cytosolic mitochondrial DNA release, a feature commonly observed in aging cells, which was accompanied by increased expression of immune and senescence-associated markers. In parallel, MFF KO mice showed glial activation and compromised dendritic integrity with disrupted excitatory/inhibitory synaptic organization and transmission and reduced extracellular matrix components. Collectively, our data support mitochondrial fission dysfunction as a potential upstream driver of aging, linking mitochondrial stress to senescence-like immune signaling, glial remodeling, and multi-scale synaptic vulnerability.