Mitochondria are the power plants of the cell, responsible for generating adenosine triphosphate (ATP), a chemical energy store molecule used to power cellular operations. The inner workings of each mitochondrion are energetic and complicated, consisting of a number of interacting protein complexes that collectively perform the work needed to manufacture ATP molecules. Mitochondrial function occupies a central position in the interaction between metabolism and aging for a number of reasons. Firstly, they generate reactive oxygen species (ROS) as a side effect of ATP production, and the flux of ROS is both damaging and a signal to the cell to step up its efforts to repair damage. A little more ROS than usual can be beneficial. Too much ROS is harmful. Secondly, some of the critical proteins in mitochondrial complexes are produced from DNA inside the mitochondria rather than in the cell nucleus, and that DNA is vulnerable to damage. Some forms of mitochondrial DNA damage can produce damaged mitochondria that cause great harm to the cell and surrounding tissue. Thirdly, cells need ATP, and reductions in ATP production have detrimental consequences over time.
There are many ways in which mitochondrial function can be altered through the removal or reduced production of a specific subunit of one of the mitochondrial protein complexes. Some such changes are disastrous, some are beneficial. Why that is the case is a complicated topic. It has a great deal to do with the balance between production of ROS and production of ATP, the needs of cells, and the reactions of cells, particularly the activation of repair and maintenance mechanisms. That balance is different in each case, and it is a slow and expensive process to run through the protein biochemistry needed to gain insight into what exactly is going on under the hood. The paper here is an example of the sort of work that takes place in this part of the field.
Mitochondria play an essential role in many important physiological processes, including aging. Mitochondrial function has been thought to gradually decline with age, while oxidative damage and mitochondrial DNA mutations accumulate. Although complete disruption of mitochondrial function is detrimental or even lethal for many eukaryotes, including humans, accumulating evidence has revealed that partial inhibition of mitochondrial function tends to increase lifespan. In C. elegans, mutations in various mitochondrial electron transport chain (ETC) genes can greatly extend lifespan; these include mutations in isp-1 and clk-1. In addition, RNAi knockdown of various mitochondrial ETC genes prolongs lifespan in yeast, worms, and fruit flies.
The effects of mitochondrial ETC genes on modulating lifespan appear to be complex. Inhibition of some ETC genes increases lifespan, whereas inhibition of others decreases or does not alter lifespan in C. elegans and Drosophila. For example, mutations in mev-1, which encodes a subunit of complex II, causes a short lifespan in worms. In addition, the underlying causes for lifespan regulation by ETC genes remain incompletely understood. For example, the roles of reactive oxygen species (ROS) production and mitochondrial function in aging and lifespan of ETC mutants can be opposite ways. One model interpreting these opposite effects is that moderate mitochondrial impairments increase lifespan until a threshold is reached, beyond which animals display wide-spread damage, shortened lifespan, or even death. Nevertheless, how mitochondrial genes modulate lifespan and whether they function in modulating lifespan in other species remain incompletely elucidated.
ATP synthase, also known as complex V of the mitochondrial respiratory chain, is the primary cellular energy-generating machinery. In mammals, ATP synthase deficiency is one of the rarer mitochondrial oxidative phosphorylation deficiencies. ATP synthase is also intimately linked to aging. In worms, genetic inhibition of the atp-2 gene, which encodes a subunit in complex V, leads to developmental delay and increased lifespan. Additionally, a genome-wide RNAi screen revealed that RNAi knockdown of subunits atp-3, atp-5, or asb-2 prolongs worm lifespan. However, the underlying mechanism for lifespan extension due to inhibition of these subunits in the ATP synthase remains unclear. As ATP synthase is highly conserved throughout evolution, understanding the role of the ATP synthase in lifespan regulation can lead to untangling of the complexity of mitochondrial ETC genes in modulating lifespan.