Every cell contains hundreds of mitochondria, a population of complex organelles that evolved from an ancient lineage of symbiotic bacteria that merged with early forms of cell to form the first eukaryotic cells. Mitochondria still act like bacteria in many ways, retaining a fragment of their original circular DNA, replicating by division, fusing together and passing around component parts, but are nonetheless now tightly integrated into cellular metabolism. Most mitochondrial genes have migrated into the cell nucleus, and a complex process of quality control known as mitophagy operates to recycle worn and damaged mitochondria.
The primary function of mitochondria is the manufacture of adenosine triphosphate (ATP), a chemical energy store molecule used to power the cell. The core of the protein machinery inside a mitochondrion that carries out this manufacture is the electron transport chain, also known as the respiratory chain. Collectively the structures of the chain are capable of building up the necessary energy to form ATP by, as one might guess from the name, reductive and oxidative chemical reactions that transport electrons along the chain. The electron transport chain consists of many distinct proteins that join together to form four protein complexes. These complexes themselves can also assemble in a number of ways to form supercomplexes. Indeed, researchers have shown that supercomplex formation is necessary for normal levels of ATP production.
Sadly, mitochondrial function (as measured by ATP production) declines with age, a consequence of damage to mitochondrial DNA and changes in gene expression that negatively impact mitochondrial structure, dynamics, and quality control. There is interest in the research community in finding ways to improve mitochondrial function. Many of the approaches demonstrated to date are essentially compensatory, in that they tend to work at any age to increase ATP production. Unfortunately near all compare poorly to the increase in mitochondrial function produced by exercise, and while we all know that exercise is a good thing, it is impossible to exercise an escape from aging. Better approaches are needed.
Today's open access paper covers a novel approach to improve mitochondrial function. Supercomplex formation in the electron transport chain is not a matter of chance, it is guided into happening by the activities of other proteins. This is usually the case for any critical function in a cell. Researchers discovered that supercomplex formation is in part steered by COX7RP, via the usual approach of disabling the expression of the COX7RP gene and observing the results. Interestingly, increasing the expression of COX7RP in genetically engineered mice in order to increase supercomplex formation in mitochondria both improves normal mitochondrial function and slows the onset of aspects of aging.
Mitochondrial Respiratory Supercomplex Assembly Factor Contributes to Lifespan Extension in Mice
Accumulating evidence from experimental animal models and human clinical studies suggests that mitochondrial function is closely associated with both lifespan extension and age-related decline. It is well established that aging is generally accompanied by a decline in mitochondrial function, which is attributed to mitochondrial DNA damage, increased oxidative stress, and deterioration of mitochondrial quality control mechanisms. These changes are characterized by reduced respiratory activity, altered mitochondrial dynamics, and increased production of reactive oxygen species (ROS). The age-related decline in mitochondrial function has been implicated in the pathogenesis of various aging-associated diseases.
We previously demonstrated that cytochrome c oxidase subunit 7a related polypeptide (COX7RP), or COX7A2L, is a critical factor that assembles mitochondrial respiratory chain complexes into supercomplexes, which is considered to modulate energy production efficiency. Whether COX7RP contributes to metabolic homeostasis and lifespan remains elusive.
We here observed that COX7RP-transgenic (COX7RP-Tg) mice exhibit a phenotype characterized by a significant extension of lifespan. In addition, metabolic alterations were observed in COX7RP-Tg mice, including lower blood glucose levels as well as reduced serum triglyceride (TG) and total cholesterol (TC) levels. Moreover, COX7RP-Tg mice exhibited elevated ATP and nicotinamide adenine dinucleotide levels, reduced ROS production, and decreased senescence-associated β-galactosidase levels. Single-nucleus RNA-sequencing (snRNA-seq) revealed that senescence-associated secretory phenotype genes were downregulated in old COX7RP-Tg white adipose tissue (WAT) compared with old WT WAT, particularly in adipocytes.
This study provides a clue to the role of mitochondrial respiratory supercomplex assembly factor COX7RP in resistance to aging and longevity extension.
View the full article at FightAging
