Fight Aging!

Mitochondria can be ejected and taken up by cells, or transferred via connections between cells, and this appears to one of the many ways in which cells communicate or attempt to assist in cases of damage. It is of great interest to the research community that intracellular mitochondria can be taken up and used by cells, given the existence of inherited diseases resulting from mitochondrial mutations, and given the late life decline in mitochondrial function that contributes to many age-related conditions. It may be possible to deliver fully functional mitochondria as a therapy, to be ingested by cells in order to repair their function.

Several startup biotech companies are working towards the infrastructure needed to use transplanted mitochondria as a therapy. To be cost-effective, these organelles would be harvested from standardized cell lines, potentially matching recipients and lines for the known human haplotypes of mitochondrial DNA. With this work in mind, it is interesting to note today's open access paper, in which researchers provide evidence for transplanted mitochondrial to be taken up preferentially by damaged cells. This is good news, provided that the mechanism of selective uptake operates in cells with age-damaged mitochondria as well as in those where mitochondrial function is compromised by other means.

Preferred Migration of Mitochondria toward Cells and Tissues with Mitochondrial Damage

Mitochondria play a fundamental role in cellular survival and growth by supplying energy in the form of ATP via oxidative phosphorylation. Isolated mitochondria can be transferred to any cell type via simple coincubation or brief centrifugation in vitro. Isolated mitochondria can also be internalized into tissues through local or systemic injection in vivo. It was suggested that mitochondrial internalization would be mediated by micropinocytosis or actin-dependent endocytosis. In animal models and patients, the injection of autologous or nonautologous mitochondria has been effective in treating injury and diseases, including ischemia/reperfusion injury, spinal cord injury, mouse fatty liver, cognitive deficits, inflammatory diseases, and Parkinson's disease.

Although the underlying mechanisms of such effects are not fully understood, it has been suggested that the transfer of healthy mitochondria (or mitochondrial transplantation) ameliorates mitochondrial defects and helps recover cellular function by increasing mitochondrial biogenesis or replacing abnormal mitochondria with healthy mitochondria. Recently, our data have demonstrated that mitochondrial transplantation attenuated the lipopolysaccharide-induced inflammation in vitro and in vivo by blockade of the activity of NFκB. Therefore, the transfer of fully functional mitochondria into defective cells or tissues could be an effective therapeutic strategy for treating mitochondrial dysfunction.

The key to successful mitochondrial transplantation therapy is the trafficking of mitochondria to the target cells, in which they can exert their biological effects. Therefore, systemically administrated mitochondria must have abilities that guide them to the sites with mitochondrial damage. Intravenously injected mitochondria might localize preferentially to damaged tissues; mitochondrial trafficking to the sites of injury is not well studied, however.

In the present study, we isolated mitochondria conjugated with green fluorescent protein (MTGFP) from stable HEK293 cells expressing TOM20 fused to an upstream green fluorescent protein (GFP). In a coculture system, MTGFP was internalized in a cell type-specific manner. We also found that selective MTGFP transplantation depended on the mitochondrial function of the receiving fibroblasts. Furthermore, compared with MTGFP injected intravenously into normal mice, MTGFP injected intravenously into bleomycin-induced idiopathic pulmonary fibrosis (IPF) mice located more abundantly in the lung tissue, suggesting that mitochondrial trafficking to damaged cells and tissues occurred.