Mitochondrial Transplant Alleviates Stress-Induced Mitochondrial Dysfunction in Rat Brains
Mitochondrial transplantation is potentially a way to restore more youthful mitochondrial function without the need for a far greater understanding of exactly how exactly mitochondria become dysfunctional with age. Cells will readily ingest mitochondria from the surrounding intercellular space and make use of them. If those mitochondria work well in comparison to the state of the cell's native mitochondria, then cell function will be improved for some time. Animal studies suggest that the effect is lasting. In that context, it is always interesting to see studies in which outcomes are assessed for mitochondrial transplantation from young animals into old animals, as in today's open access paper.
Other approaches to reducing the age-related decline in mitochondrial function have been implemented based on a combination of advances in scientific understanding and fortunate discoveries in small molecule screens. These largely appear to work at least in part via improved mitophagy, the quality control process responsible for recycling worn and broken mitochondria. Unfortunately, these treatments fail to improve on exercise when it comes to enhancing measures of health. This category of interventions in includes increasing NAD levels via delivery of precursors, urolithin A and its effects on mitochondrial dynamics, mitochondrially targeted antioxidants such as mitoQ, and so forth.
While potentially more interesting approaches are under development, such as copying mitochondrial DNA into the cell nucleus to provide a backup source of proteins when mitochondrial DNA becomes damaged, these are still very much works in the progress. Even given that a company has held clinical trials for a gene therapy to introduce a backup copy of one mitochondrial gene, there are still a range of other mitochondrial genes to deal with in this way. Mitochondrial transplantation is somewhat closer to the clinic, however. The only significant roadblock is the efficient manufacture of large numbers of mitochondria, and several venture funded companies are working on solutions.
Apoptosis is common and often comorbid with aging and stress-related mood disorders. Evidence suggests that fresh mitochondria could reverse age-related dysfunctions in organs, especially in the brain. Therefore, this study investigated the effect of young mitochondria administration on the apoptosis process in the prefrontal cortex (PFC) of aged rats exposed to chronic stress.
Aged (22 months old) male rats were randomly assigned into four groups: aged control (AC), aged rats treated with young mitochondria (A+M), aged rats subjected to chronic stress for four weeks (A+St), and aged rats subjected to chronic stress and treated with young mitochondria (A+St+M). A+M and A+St+M groups received a single intracerebroventricular injection (10 μl) of fresh mitochondria isolated from the brain of young rats. Finally, the levels of malondialdehyde (MDA), cytochrome c (Cyt c), Bax, Bcl-2, and Caspase-3 expression were investigated in the PFC.
The results of the present study demonstrated that the transplantation of young mitochondria ameliorated oxidative stress in the PFC of aged and chronic stress-exposed aged rats, as indicated by diminished MDA levels and reduced Cyt c release. Young mitochondria also markedly attenuated apoptosis markers in the PFC of aged and chronic stress-exposed aged groups, which was characterized by down-regulated expression levels of pro-apoptotic proteins, Bax and caspase-3, and up-regulated expression levels of anti-apoptotic protein Bcl-2. These results suggest mitochondrial transplant therapy could reverse cell viability and mitochondrial dysfunction-induced apoptosis in the PFC tissue of aged rats subjected to stressful stimuli.