Bisphenol-A impairs hippocampal neurogenesis by disrupting Kinesin-1-dependent mitochondrial trafficking

Mitochondrial trafficking ensures proper distribution of mitochondria in energy-demanding neural stem cells (NSCs) and neurons, by supplying ATP for neuronal function and survival. We studied the effects of xenoestrogen bisphenol-A (BPA), found in consumable plastic products, on axonal bi-directional mitochondrial trafficking/movement in neurons. Time-lapse live-cell imaging revealed that BPA exposure impaired anterograde and retrograde axonal mitochondrial trafficking, resulting in altered mitochondrial distribution and density in hippocampal NSCs-derived neurons. In silico docking studies identified plausible binding of BPA with Kinesin-1, Dynein, and Syntaphilin (SNPH). BPA postnatal exposure reduced mRNA expression and protein levels of mitochondrial trafficking motor proteins Kinesin-1(KIF5A) and Dynein, and increased mitochondrial static anchor protein SNPH in the rat hippocampus. BPA significantly reduced co-localization of KIF5A and Dynein with TOMM20, Nestin & β-III tubulin in vitro and Sox-2 & NeuN in vivo, and increased SNPH co-localization with TOMM20, Nestin & Sox-2, indicating impaired mitochondrial trafficking during NSCs proliferation and differentiation. Transmission Electron Microscopy revealed reduced axonal mitochondrial density, synaptic density, increased damaged mitochondria, and synaptic loss following BPA exposure. Pharmacological inhibition (Monastrol) and activation (Kinesore) of KIF5A mediated mitochondrial transport caused aggravated and mitigated BPA-mediated impairments in NSCs proliferation and neuronal differentiation. BPA-mediated inhibition of mitochondrial distribution, bioenergetics, and synaptic function was reversed by Kinesore, by increasing mitochondrial & synaptic density, mitochondrial movement, and reducing damaged synapses & mitochondria, leading to cognitive improvements. These findings implicate the role of Kinesin-1(KIF5A) in reversing BPA-mediated impaired mitochondrial transport, reduced hippocampal neurogenesis, and cognitive deficits in rats.