Mitochondrial Complex I, a Possible Sensible Site of cAMP Pathway in Aging

Abstract

In mammals during aging, reactive oxygen species (ROS), produced by the mitochondrial respiratory chain, cause oxidative damage of macromolecules leading to respiratory chain dysfunction, which in turn increases ROS mitochondrial production. Many efforts have been made to understand the role of oxidative stress in aging and age-related diseases. The complex I of the mitochondrial respiratory chain is the major source of ROS production and its dysfunctions have been associated with several forms of neurodegeneration, other common human diseases and aging. Complex I-ROS production and complex I content have been proposed as the major determinants for longevity. The cAMP signal has a role in the regulation of complex I activity and the decrease of ROS production. In the last years, an increasing number of studies have attempted to activate cAMP signaling to treat age-related diseases associated with mitochondrial dysfunctions and ROS production. This idea comes from a long-line of studies showing a main role of cAMP signal in the memory consolidation mechanism and in the regulation of mitochondrial functions. Here, we discuss several evidences on the possible connection between complex I and cAMP pathway in the aging process.

Deregulation of multiple mechanisms shapes the onset ofLAMA2-congenital muscular dystrophy

“…Complex I was increased in Lama2 -deficient cells ( Figure 1H ), while the remaining complexes remained unchanged ( Supplementary Figure 2B ). Complex I is a key source of ROS production in the mitochondria, and increased levels of complex I have been associated with aging 26,27 . Importantly, decreased mitochondrial number has also been linked to skeletal muscle aging 28 .…”

Alterations in Mitochondrial Oxidative Phosphorylation System: Relationship of Complex V and Cardiac Dysfunction in Human Heart Failure

“…It is also considered the major source of ROS production [ 29 ]. Complex I has three functional modules named N-module (NADH binding and oxidation), Q-module (electron transfer to ubiquinone), and P-module (proton pumping) [ 30 ]. The different modules can be separated, and also, according to the types of proteins and subunits, including subunits of the α-subcomplex, β-subcomplex, iron–sulfur proteins, flavoproteins, mtDNA encoded proteins, acyl-carrier proteins, subunits C, and assembly proteins.…”

Functional and Morphological Differences of Muscle Mitochondria in Chronic Fatigue Syndrome and Post-COVID Syndrome

“…Booth et al proposed a lack of essential substrates and partial blocking of the translocator protein sites in the mitochondria of ME/CFS patients [17], possibly contributing to less energy supply in these patients. If complex I, which is the entry point of NADH-reducing equivalents in the mitochondrial respiratory chain catalyzing the electron transport from NADH to ubiquinone, is only "insufficiently pumping" by impaired protein assembly, a logical consequence could be the observed diminished exercise capacity in PCS: the transmembrane potential, derived by complex I through coupling to the proton pump from the matrix to the intermembrane space, drives ATP formation by complex V [30], and the impaired ATP supply may result in the observed decreased performance.…”