Improving Mitochondrial Complex I Function in Aged Tissues Might Be Achieved via Upregulation of Just a Few Component Proteins
Mitochondria are the power plants of the cell, several hundred working away in every cell to package the chemical energy store molecule adenosine triphosphate (ATP). At the heart of this energetic process taking place inside every mitochondrion is the electron transport chain, consisting of several complicated protein complexes, each made up of multiple subunit proteins that are manufactured from their genetic blueprints somewhat independently of one another.
Research into other complicated protein complexes, such as the proteasome, has shown that the relatively slow pace of production of one of the protein subunits can be rate-limiting to the formation of the complex as a whole. Overall function can thus be improved by increasing expression of just that one protein subunit. See the work on the β5 subunit of the fly proteasome, for example.
In today's open access paper, researchers report that a similar situation may exist for complex I of the electron transport chain in mitochondria. In the past, it has been demonstrated in animal studies that impairing expression of components of complex I can produce a compensatory response that leads to improved cell function and slower pace of aging. It is perhaps the case that increased expression of some components can also achieve a slowing of aging by compensating in part for the age-related decline in mitochondrial function.
This is probably not the best approach to the mitochondrial dysfunction of aging, however. At the present time, replacement of mitochondria throughout the body seems the most feasible near future approach, followed by systemic partial reprogramming to restore youthful gene expression of important mitochondrial proteins. The latter approach has sizable technical issues relating to delivery and tissues in which reprogramming may be harmful, while the former is really only a logistics challenge - the production of suitable mitochondria at scale, and to a high enough quality.
Studies in Drosophila have identified several genetic manipulations of mitochondrial proteins that have shown some promise in increasing lifespan. For example, induction of Dynamin-related protein 1 (Drp1), which is a major regulator of mitochondrial fission, during midlife in Drosophila increases lifespan. Similarly, forced expression of the yeast alternative NADH:ubiquinone oxidoreductase, which catalyzes the transfer of electrons from NADH to ubiquinone via FAD without pumping protons across the mitochondrial inner membrane increases lifespan. Further, overexpression of the alternative NADH:ubiquinone oxidoreductase reduces reactive oxygen species (ROS) production and increases several markers of complex 1 (CI) activity.
Paradoxically, a restrained knockdown of several CI proteins also enhances longevity. While the exact mechanisms involved in triggering the increased lifespan caused by mild CI disruption are still being unraveled, compensatory mitochondrial stress signaling cascades seem to contribute prominently. However, the question of whether boosting the expression of individual CI subunits can extend lifespan remains uncharted.
The boot-shaped respiratory complex I (CI) consists of a mitochondrial matrix and membrane domain organized into N-, Q- and P-modules. The N-module is the most distal part of the matrix domain, whereas the Q-module is situated between the N-module and the membrane domain. The proton-pumping P-module is situated in the membrane domain.
We explored the effect of aging on the disintegration of CI and its constituent subcomplexes and modules in Drosophila flight muscles. We find that the fully-assembled complex remains largely intact in aged flies. And while the effect of aging on the stability of many Q- and N-module subunits in subcomplexes was stochastic, NDUFS3 was consistently down-regulated in subcomplexes with age. This was associated with an accumulation of many P-module subunits in subcomplexes. The potential significance of these studies is that genetic manipulations aimed at boosting, perhaps, a few CI subunits may suffice to restore the whole CI biosynthesis pathway during muscle aging.