Fight Aging!

Mitochondria are the power plants of the cell, producing the chemical energy store molecule adenosine triphosphate (ATP) to power cellular biochemistry. Mitochondrial function declines with age, in part due to damage to mitochondria DNA and in part due to changes in nuclear gene expression that affect proteins needed by mitochondria. This is considered an important contribution to age-related degeneration, particularly in tissues such as muscle and brain that have high energy needs.

Cells will take up mitochondria from their surroundings and make use of them. Studies in mice have indicated that transplantation of mitochondria harvested from cell cultures can produce lasting benefits. The processes of aging that diminish mitochondrial function take a while to operate, and youthful mitochondria can improve function for an extended period of time. The challenge here is that mice are small and people are large; reliable production of the large numbers of mitochondria needed is the primary hurdle preventing clinical use of this approach in old people.

A number of companies are working on the mitochondrial manufacturing challenge, including cellvie and Mitrix Bio. In today's open access paper, an academic group describes a potential approach to the problem, though this is aimed at local injection into cartilage. The goal of whole-body infusions of replacement mitochondria might require another two orders of magnitude of increased scale, and it remains to be seen if this approach will work at that level.

Organelle-tuning condition robustly fabricates energetic mitochondria for cartilage regeneration

Mitochondria are vital organelles whose impairment leads to numerous metabolic disorders. Mitochondrial transplantation serves as a promising clinical therapy. However, its widespread application is hindered by the limited availability of healthy mitochondria, with the dose required reaching up to 10^9 mitochondria per injection/patient. This necessitates sustainable and tractable approaches for producing high-quality human mitochondria.

In this study, we demonstrated a highly efficient mitochondria-producing strategy by manipulating mitobiogenesis and tuning organelle balance in human mesenchymal stem cells (MSCs). Utilizing an optimized culture medium (mito-condition) developed from our established formula, we achieved an 854-fold increase in mitochondria production compared to normal MSC culture within 15 days. These mitochondria were not only significantly expanded but also exhibited superior function both before and after isolation, with ATP production levels reaching 5.71 times that of normal mitochondria.

Mechanistically, we revealed activation of the AMPK pathway and the establishment of a novel cellular state ideal for mitochondrial fabrication, characterized by enhanced proliferation and mitobiogenesis while suppressing other energy-consuming activities. Furthermore, the in vivo function of these mitochondria was validated in the mitotherapy in a mouse osteoarthritis model, resulting in significant cartilage regeneration over a 12-week period. Overall, this study presented a new strategy for the off-the-shelf fabrication of human mitochondria and provided insights into the molecular mechanisms governing organelle synthesis.