# Coenzyme Q at the Hinge of Health and Metabolic Diseases
## 5 Role of CoQ in Aging and Age-Associated Metabolic Disorders  
The accumulation of dysfunctional mitochondria is a shared feature of both aging and metabolic disorders [156; 157; 158; 159]. Evidence indicating the essential role of mitochondrial physiology in the increasing dysfunction of tissues and organs during aging has been accumulating over the last few years [160; 161]. This indicates that any therapy able to main  
Figure 2: Causes of secondary CoQ deficiency. Mechanisms proposed to trigger the secondary variant are grouped in several categories (G1 to G6) indicated in different colors. The synthesis of CoQ can be reduced by defects in proteins implicated directly or indirectly in the assembly and proper respiratory machinery functioning (G1 (blue) and G3 (red)). In orange (G2) are the essential proteins for the maintenance of intact mtDNA. Point mutations in mitochondrial aminoacyl-tRNA synthetases are also associated with low CoQ levels. The stability of Q-synthome depends on ER-mitochondrial contact sites (ERMES) and the cholesterol synthesis pathway (G4 (purple)). Defects in the proteins implicated in the transport of several metabolites, such as glucose or Fe\({}^{2+}\), throughout to plasm or mitochondrial membrane cause channelopathies, marked in green (G5). The mechanisms to maintain mitochondrial mass by processes such as fusion-fission proteins, MFN1, and MFN2 (G6) are shown in yellow. tain a balanced mitochondrial turnover and dynamics can delay age-associated metabolic diseases and improve functionality during the progression of aging [1; 4; 39]. The essential role of CoQ in the maintenance of mitochondrial activities and in the prevention of oxidative damage in cells and plasma lipoproteins points to its importance in aging and in age-related diseases [1; 162]. However, it is not clear if the decrease in CoQ levels associated with aging is the cause of mitochondrial dysfunction or a consequence of the deterioration of the turnover and dynamics of mitochondria found in metabolic diseases and aging [157; 160; 163]. We can consider that the secondary CoQ deficiency associated with aging may be a consequence of OXPHOS dysfunction [126]. Several CoQ biosynthesis genes were downregulated in mice showing impaired mtDNA gene expression [126]. Many components of the CoQ-synthome suffered a clear decrease in mitochondria: COQ3, COQ5, COQ6, COQ7, COQ8A/ADCK3, COQ9, and COQ10A. On the other hand, two of these enzymes (PDSS2 and COQ8B/ADCK4) increased, indicating a different response of the members of the synthome to mitochondrial dysfunction [126]. Additionally, COQ8A/ADCK3 and COQ8B/ADCK4 are regulated depending on the glycolytic or respiratory conditions, indicating a response to the metabolic conditions [164]. It has been recently reported that in glioma cells, the inhibition of CoQ biosynthesis is associated with the stabilization of HIF-1 and the switch toward glycolysis, introducing a mechanism in the regulation of the metabolism and the development of cancer [165]. The decrease in CoQ levels found in mutants and in aged animals could be a response to the equilibrium to maintain a balanced activity of the ETC. However, we cannot discard a side effect of OXPHOS dysfunction that affects activities in the inner mitochondrial membrane that regulate CoQ synthesis [67], and the transport of proteins into the mitochondrial matrix that can destabilize the CoQ-synthome [126]. Interestingly, the maintenance of balanced mitochondrial dynamics is essential to avoid mitochondrial dysfunction during aging and metabolic diseases [156]. The transport of polyphenyl pyrophosphate from endoplasmic reticulum to mitochondria is severely affected in mitofusin2 (MFN2) KO mice and causes CoQ deficiency [147]. MFN2 is directly involved in mitochondrial fusion [166], and also in the tethering of mitochondria to the ER [167].