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 (NSC) and neurons 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 NSC-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 SNPH in the rat hippocampus. BPA significantly reduced colocalization of KIF5A and dynein with TOMM20, Nestin and β-III tubulin in vitro and Sox-2 and NeuN in vivo and increased SNPH colocalization with TOMM20, Nestin, and Sox-2, indicating impaired mitochondrial trafficking during NSC proliferation and differentiation. Transmission electron microscopy revealed reduced axonal mitochondrial density, synaptic density, increased damaged mitochondria, and synaptic loss following BPA exposure. Pharmacological activation (kinesore; a modulator of kinesin-1 activity) of KIF5A-mediated mitochondrial transport mitigated BPA-mediated impairments in NSC proliferation and neuronal differentiation. BPA-mediated inhibition of mitochondrial distribution, bioenergetics, and synaptic function was reversed by kinesore, as evidenced by increased mitochondrial and synaptic density, increased mitochondrial motility, and reduced damage to synapses and 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.