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.

Keywords: aging; cAMP; complex I; mitochondria; signaling.

Figure 1

Schematic representation of mammalian complex I. (A) Complex I with “L” shape is shown in three distinct modules: N-module (in green), Q-module (in pink) and P-module (in blue). N and Q modules constitute the hydrophilic arm of complex I, exposed in the matrix [45]. The P-module constitutes the hydrophobic arm of the complex embedded in the mitochondrial inner membrane (MIM) [45]. The oxidation of NADH by FMN generates the electrons transfer, through the seven iron–sulfur clusters (yellow spheres), to ubiquinone molecule [44]. The reduction of ubiquinone induces conformational changes in the P-module. This results in proton pumping from matrix to intermembrane space. The reduced FMN, and probably the N2 iron–sulfur cluster, can also react with molecular oxygen (O₂) to form superoxide anion (O₂^·-). (B) The complex I subunits belonging to N, Q and P modules are reported [47,48,49,50,51].

Figure 2

Several alterations have been found to affect complex I during aging process. A functional decline, associated with a decrease of complex I content, has been observed [60,65]. The complex I-dependent ROS production increases with aging in accordance with the increase of oxidation of complex I subunits [2,5,61,62]. Additionally, the superassembly of complex I has been found decreased during aging [93]. Very interesting, a dangerous effect of the subunits belonging to peripheral hydrophilic arm has been observed. In particular, the peripheral subunits hydrophilic arm can form a subcomplex I that oxidize NADH without the proton pumping but producing ROS [71]. cAMP pathway has been found altered during aging process. The cAMP/PKA cascade promotes complex I activity [8,10,55] by increasing the mitochondrial import of the NDUFS4 subunit [98]. Once in mitochondria, the level of the NDUFS4 protein, as well as, the other peripheral subunits, is sustained by mitochondrial cAMP pool [31]. This can allow a dynamic exchange between the new imported subunits and the already assembled probably oxidized ones, as found for NDUFV2 and NDUFS4 [31,37,55]. The PKA-dependent phosphorylation of the NDUFS4 subunit is found associated with the cAMP-dependent increase of complex I assembly in supercomplex [58].