Hippocampal Mitochondrial Transplantation Alleviates Age-Associated Cognitive Decline via Enhancing Wnt Signaling and Neurogenesis

Abstract

Gradual cognition decline and mitochondrial dysfunction are two notable changes closely associated with aging. Enhancing mitochondrial function has been assumed to be antiaging. However, most current mitochondria-promoting agents usually target 1-2 aspects of mitochondrial function. In the present study, we transplanted mitochondria isolated from young mice into the hippocampus of aged mice, which presumably boost mitochondrial function more thoroughly, examined the effects on cognition, and explored the possible underlying mechanism. Our data showed that exogenous mitochondria were efficiently internalized by nestin-positive neural progenitors in the hippocampus. Mitochondrial transplantation quickly increased ATP levels, enhanced the activity of mitochondrial complexes I, II, and IV, and decreased Tom20 expression in the hippocampus. In regard of cognitive function, mitochondria-treated mice displayed a remarkable improvement of novel object recognition and spatial memory. Utilizing the Wnt signaling reporting mouse line, TOPGAL mice, we detected activated canonical Wnt signaling in the neural progenitors of the mitochondria-treated hippocampus. Further, BrdU labeling showed that exogenous mitochondria significantly stimulated neural progenitor neurogenesis and proliferation. Taken together, our data demonstrated that exogenous mitochondria from young mice might be a novel way of rejuvenating the function of hippocampal neural progenitors to exert antiaging effects.

Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation

“… Disease Species/Applied Model Source of Mitochondria Route of Transplantation Ref. Parkinson’s disease Rat Allogeneic/xenogeneic Pep-1-labeled mitochondria Injection into the medial forebrain bundle [ 154 ] Parkinson’s disease Mouse Human hepatoma cells Intravenous injection [ 169 ] Parkinson’s disease Rat Liver allogeneic mitochondria conjugated with Pep-1 Intranasal infusion [ 165 ] Alzheimer’s disease Mouse HeLa cell-derived mitochondria Tail intravenous injection [ 162 , 177 ] Cognitively impaired aged mice Mouse Liver allogeneic mitochondria isolated from young mice Injected into the hippocampus of aged mice [ 178 ] Diabetes-associated cognitively impaired mice Mouse Platelet-derived mitochondria Intracerebroventricular injection [ 179 ] Chronic mild stressed—aged rats Rat …”

Mitochondrial Transplantation Promotes Remyelination and Long-Term Locomotion Recovery following Cerebral Ischemia

“…Recently, in vivo transplantation of healthy mitochondria has been proposed as an effective way to boost mitochondria function and exert neuroprotection [ 7 , 8 ]. For example, mitochondrial transplantation exerted remarkable beneficial effects in preventing secondary injury in traumatic brain injury and cognitive decline in aging [ 9 , 10 ]. High metabolic requirement was observed during the myelination process of oligodendrocyte precursor cells (OPCs) [ 11 ].…”