Fight Aging!

Every cell contains hundreds of mitochondria, hard at work to produce the chemical energy store molecule adenosine triphosphate (ATP), used to power cellular activities. Mitochondria are complex structures, the evolved descendants of ancient symbiotic bacteria that are now integrated into the cell. At their center is the electron transport chain, a collection of protein complexes that conducts the energetic chemical reactions needed to make ATP. Mitochondria bear copies of a remnant circular genome, DNA distinct from that in the cell nucleus, which encodes some of the mitochondrial proteins necessary for mitochondrial function. The sequences for other mitochondrial proteins have migrated over time into the nuclear DNA.

A great deal of evidence points to a significant role for mitochondrial dysfunction in degenerative aging. This arises in part due to damage to mitochondrial DNA, which is less well protected and maintained than is the case for nuclear DNA. It is also a matter of age-related changes in the expression of mitochondrial genes in the cell nucleus, which appear to affect both function of mitochondria and the clearance of damaged mitochondria via mitophagy, a form of selective autophagy. Mitochondria are dynamic organelles, constantly dividing and fusing together, and imbalances in this behavior can impair mitophagy, as well as lead to smaller numbers of mitochondria than would be optimal.

Today's open access paper takes a look at the proximate outcomes rather than the proximate causes of mitochondrial dysfunction. Firstly a loss of ATP production, and secondly an increase in the production of oxidative molecules as a side-effect of the energetic activities of the electron transport chain. Too much oxidative stress on cells is damaging to their function, and dysfunctional mitochondria are the primary culprit when it comes to producing that oxidative stress.

Aging Triggers Mitochondrial Dysfunction in Mice

The current study sought to investigate the effects of aging on cardiac mitochondrial function by examining various parameters of mitochondrial respiration, ROS production, ATP production, mitochondrial membrane potential, mitochondrial swelling, and proton leakage. The findings of this study suggest that the aging process has a significant impact on cardiac mitochondrial function.

One of the most important findings of this study was that cardiac mitochondrial oxygen consumption was significantly lower in old mice than in young mice. Besides showing a slight reduction in oxygen consumption by complex I under the phosphorylative state (state 3), we observed a strong reduction in oxygen consumption by complex II state 3. This finding suggests that aging reduces mitochondrial respiratory capacity. Furthermore, this dysfunction in the complex II state 3 may indicate a characteristic failure of oxidative phosphorylation during aging. The decreased respiratory capacity in old mice could be attributed to an age-related decline in the expression and activity of electron transport chain complexes or a decrease in the number of functional mitochondria.

Additionally, our study demonstrated that under complex I and complex II state 3 stimulation, the production of mitochondrial reactive oxygen species (ROS) was higher in the hearts of older animals than in younger animals. This finding raises the possibility that the age-related decline in the antioxidant defense system, which lead to results in oxidative stress and cellular damage and may be the cause of the increased ROS production. These results are in agreement with the previously published studies that describe transcriptional changes in pathways related to ROS in the heart. Our study also showed that the mitochondrial ATP production under stimulation of complex I and complex II state 3 was significantly lower in the hearts of old versus young mice. This finding suggests that the production of mitochondrial ATP declines with age. The reduction in the number of functional mitochondria or the age-related decline in the activity of the electron transport chain complexes, which produce the proton gradient for ATP synthesis, may be the cause of this decline in ATP production

Interesting data, in particular, are the significantly depolarized mitochondrial membrane potential in the hearts of old versus young mice. This result explains the increase in mitochondrial ROS production in old mice once a membrane depolarization reduces the rate of electron flow, increasing the degree of electronic reduction in the phosphorylative chain and generating more ROS. Additionally, it explains the reduction in the production of ATP because the membrane depolarization also reduces the proton gradient, reducing the proton driving force through the ATP-synthase and impairing its functioning. The age-related changes in the expression and activity of the electron transport chain complexes or the mitochondrial uncoupling proteins may be the cause of the elevated mitochondrial membrane potential. Finally, the study showed that under complex I and II state 3 stimulation, the mitochondrial proton leakage was significantly higher in old mice compared to young mice hearts. This finding indicates that the mitochondrial proton leakage increases with aging, possibly as a result of the aging-related decline in activity of the electron transport chain complexes or the mitochondrial uncoupling proteins.