Kisspeptin preserves mitochondrial function by inducing mitophagy and autophagy in aging rat brain hippocampus and human neuronal cell line

It has become amply clear that mitochondrial function defined by quality, quantity, dynamics, homeostasis, and regulated by mitophagy and mitochondrial biogenesis is a critical metric of human aging and disease. As a consequence, therapeutic interventions that can improve mitochondrial function can have a profound impact on human health and longevity. Kisspeptins are neuropeptides belonging to the family of metastasis suppressors that are known to regulate functions like fertility, reproduction, and metabolism. Using SKNSH cell line, hippocampus explant cultures and hippocampus of aging Wistar rat models, we show that Kisspeptin-10 (Kp) induces autophagy and mitophagy via calcium, Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), and Unc-51 like autophagy activating kinase (ULK1) signaling pathway that is independent of mammalian target of rapamycin (mTOR). Intriguingly, Kp administration in vivo also results in the enhancement of mitochondrial number, complex I activity, and Adenosine Triphosphate (ATP) levels. This study uncovers potential effects of Kp in protecting mitochondrial health and as a possible therapeutic intervention to hippocampus associated impairments such as memory, cognitive aging, and other diseases linked to mitochondrial dysfunction. •Kisspeptin-10 stimulates autophagy/ mitophagy in rodent hippocampus and SKNSH cell lines.•Kisspeptin-10 induces autophagy/mitophagy via calcium, CaMKKβ, AMPK, and ULK1 signaling•Kisspeptin-10 preserves mitochondrial function by enhancing mitochondrial number, complex I activity and ATP levels in vivo