Vitamin B12-folic acid supplementation improves memory by altering mitochondrial dynamics, dendritic arborization, and neurodegeneration in old and amnesic male mice.

Memory impairment during aging and amnesia is attributed to compromised mitochondrial dynamics and mitophagy and other mitochondrial quality control mechanisms. Mitochondrial dynamics involves the continuous process of fission and fusion of mitochondria within a cell and is a fundamental mechanism for regulating mitochondrial quality and function. An extensive range of potential nutritional supplements has been shown to improve mitochondrial health, synaptic plasticity, and cognitive functions. Previous findings revealed that supplementation of vitamin B12-folic acid reduces locomotor deficits and mitochondrial abnormalities but enhances mitochondrial and neuronal health. The present study aims to explore the impact of combined vitamin B12-folic acid supplementation on mitochondrial dynamics, neuronal health, and memory decline in old age and scopolamine-induced amnesia, which remains elusive. The results demonstrated that supplementation led to a noteworthy increase in recognition and spatial memory and expression of memory-related protein BDNF in old and amnesic mice. Moreover, the decrease in the fragmented mitochondrial number was validated by the downregulation of mitochondrial fission p-Drp1 (S616) protein and the increase in elongated mitochondria by the upregulation of mitochondrial fusion Mfn2 protein. The increased spine density and dendritic arborization in old and amnesic mice upon supplementation were confirmed by the enhanced expression level of PSD95 and synaptophysin. Furthermore, supplementation reduced ROS production, inhibited Caspase-3 activation, mitigated neurodegeneration, and enhanced mitochondrial membrane potential, ATP production, Vdac1 expression, myelination, in old and amnesic mice. Collectively, our findings imply that combined supplementation of vitamin B12-folic acid improves mitochondrial dynamics and neuronal health, and leads to recovery of memory during old age and amnesia.

Mdivi-1 Rescues Memory Decline in Scopolamine-Induced Amnesic Male Mice by Ameliorating Mitochondrial Dynamics and Hippocampal Plasticity.

Memory loss, often known as amnesia, is common in the elderly population and refers to forgetting facts and experiences. It is associated with increased mitochondrial fragmentation, though the contribution of mitochondrial dynamics in amnesia is poorly understood. Therefore, the present study is aimed at elucidating the role of Mdivi-1 in mitochondrial dynamics, hippocampal plasticity, and memory during scopolamine (SC)-induced amnesia. The findings imply that Mdivi-1 significantly increased the expression of Arc and BDNF proteins in the hippocampus of SC-induced amnesic mice, validating improved recognition and spatial memory. Moreover, an improved mitochondrial ultrastructure was attributed to a decline in the percentage of fragmented and spherical-shaped mitochondria after Mdivi-1 treatment in SC-induced mice. The significant downregulation of p-Drp1 (S616) protein and upregulation of Mfn2, LC3BI, and LC3BII proteins in Mdivi-1-treated SC-induced mice indicated a decline in fragmented mitochondrial number and healthy mitochondrial dynamics. Mdivi-1 treatment alleviated ROS production and Caspase-3 activity and elevated mitochondrial membrane potential, Vdac1 expression, ATP production, and myelination, resulting in reduced neurodegeneration in SC mice. Furthermore, the decline of pro-apoptotic protein cytochrome-c and increase of anti-apoptotic proteins Procaspase-9 and Bcl-2 in Mdivi-1-treated SC-induced mice suggested improved neuronal health. Mdivi-1 also increased the dendritic arborization and spine density, which was further corroborated by increased expression of synaptophysin and PSD95. In conclusion, the current study suggests that Mdivi-1 treatment improves mitochondrial ultrastructure and function through the regulation of mitochondrial dynamics. These changes further improve neuronal cell density, myelination, dendritic arborization, and spine density, decrease neurodegeneration, and improve recognition and spatial memory. Schematic presentation depicts that Mdivi-1 rescues memory decline in scopolamine-induced amnesic male mice by ameliorating mitochondrial dynamics and hippocampal plasticity.

Mitophagy: A promising therapeutic target for neuroprotection during ageing and age-related diseases.

Mitochondria and mitochondria-mediated signalling pathways are known to control synaptic signalling, as well as long-lasting changes in neuronal structure and function. Mitochondrial impairment is linked to synaptic dysfunction in normal ageing and age-associated neurodegenerative ailments, including Parkinson's disease (PD) and Alzheimer's disease (AD). Both proteolysis and mitophagy perform a major role in neuroprotection, by maintaining a healthy mitochondrial population during ageing. Mitophagy, a highly evolutionarily conserved cellular process, helps in the clearance of damaged mitochondria and thereby maintains the mitochondrial and metabolic balance, energy supply, neuronal survival and neuronal health. Besides the maintenance of brain homeostasis, hippocampal mitophagy also helps in synapse formation, axonal development, dopamine release and long-term depression. In contrast, defective mitophagy contributes to ageing and age-related neurodegeneration by promoting the accumulation of damaged mitochondria leading to cellular dysfunction. Exercise, stress management, maintaining healthy mitochondrial dynamics and administering natural or synthetic pharmacological compounds are some of the strategies used for neuroprotection during ageing and age-related neurological diseases. The current review discusses the impact of defective mitophagy in ageing and age-associated neurodegenerative conditions, the underlying molecular pathways and potential therapies based on recently elucidated mitophagy-inducing strategies.

Alterations in hippocampal mitochondrial dynamics are associated with neurodegeneration and recognition memory decline in old male mice.

Mitochondrial dynamics is a key process that modulates the ultrastructure, quality and function of mitochondria. It is disrupted in numerous major neurodegenerative disorders including Parkinson's, Alzheimer's and Huntington's disease. Mitochondrial dysfunction has been correlated with the loss of memory. Previous studies suggest the involvement of Vdac1 and Drp1 in outer mitochondrial membrane permeabilization and promotion of mitochondrial fragmentation through Drp1 phosphorylation at S616. However, alterations in mitochondrial dynamics with respect to aging, memory loss and neurodegeneration remain unexplored. Therefore, the present study focuses on the involvement of mitochondrial dynamics in neurodegeneration and recognition memory decline during aging. The recognition memory decline was validated by the novel object recognition test and measurement of hippocampal Arc protein level during aging. The ultrastructure analysis revealed a decline in mitochondrial length and area, while an increase in the number of fragmented, round and disrupted mitochondria in the hippocampus during aging. Disruption was also evident in mitochondrial cristae and membrane with advancing age. The change in mitochondrial morphology was corroborated by an increase in the expression of phospho-Drp1 (S616) and Cyt-c proteins but decline in Mfn2, LC3B, Vdac1, Bcl-XL and Bcl-2 proteins in the hippocampus during aging. Taken together, our findings reveal that an increase in the expression of phospho-Drp1 (S616) and decrease in Mfn2 and LC3B proteins in the hippocampus bring about a reduction in mitochondrial length and area, and rise in mitochondrial fragmentation leading to reduced neuronal cell density, increased neurodegeneration and recognition memory decline in old male mice. Diagram depicts the increase in hippocampal mitochondrial fragmentation during aging of mice. Increased mitochondrial fragmentation causes distorted mitochondrial function such as decrease in ATP/ADP transportation due to decrease in Vdac1 protein level and increase in oxidative damage. These alterations result in hippocampal neurodegeneration and consequently impairment in recognition memory during aging.