# Coenzyme Q at the Hinge of Health and Metabolic Diseases
## 4 CoQ Deficiency Syndrome
### Secondary CoQ Deficiency Due to Mitochondrial Dysfunction  
Secondary CoQ deficiencies were found in affected OXPHOS or non-OXPHOS processes and also in non-mitochondrial process [14; 122], and are much more frequent and diverse than primary CoQ deficiency [122]. Table 1 includes those published cases of secondary CoQ deficiency due to mitochondrial dysfunction. The mechanisms underlying these secondary diseases are poorly understood, but they can be categorized into several groups according to the origin of CoQ deficit: (1) disorders of the OXPHOS system; (2) pathogenic variants of nuclear and mitochondrial DNA-encoded proteins; (3) defects in other enzymes upstream of OXPHOS; (4) cholesterol metabolic impairment; (5) defects in protein carriers; and (6) defects in mitochondrial homeostasis. \begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Group of** & & & & & \\
**Disorders** & **Gene** & **Function** & **Diagnosis** & \begin{tabular}{c} **Clinical Phenotype** \\ **Described in Humans** \\ \end{tabular}  & **Refs. ** \\ \hline \multirow{6}{*}{G1: Disorders due to impairment oxidative phosphorylation (OXPHOS) system} & \multirow{2}{*}{NDUFS4} & \multirow{2}{*}{NDUFS4} & \multirow{2}{*}{ \begin{tabular}{c} Defects on assembly of functional complex I \\ \end{tabular}  } & \multirow{2}{*}{\ \begin{tabular}{c} Legish syndrome \\ \end{tabular}  } & \multirow{2}{*}{
\begin{tabular}{c} Neurological \\ symptoms and lactic \\ acidosis \\ \end  
The first group of these diseases is related to the essential role of CoQ in the function of ETC. Therefore, the impairment of this system promotes mitochondrial bioenergetic disorders such as defects in proteins like BSC1L, necessary for assembling CIII [123], the CI subunit NDUFSA [124; 125], and the mitochondrial protease PARL, necessary for the processing of TTC19 required for CIII activity [67]. In these cases, the reduction in CoQ levels could be the cause of a negative feedback of CoQ biosynthesis by decreasing the activity of respiratory complexes. \begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Group of** & **Gene** & **Function** & **Diagnosis** & **Clinical Phenotype** & **Refs. ** \\ \hline \hline \multirow{9}{*}{G4: metaplicasem impairment} & & & [PERSON]’s disease, [PERSON]’s disease, mitochondrial Ca2+ & & \\  & & & & [PERSON]’s disease, and & \\  & & & mitochondrial Ca2+ & amyotrophic & \\  & & & uptake & lateral sclerosis with associated & Typical symptoms in neurodegenerative diseases & \\  & & & & & \\ G4: Cholesterol metabolism & & & & & \\ \cline{2-5}  & 3-Hydroxy-3- & & & & \\ Methyl  
The maintenance of DNA copy number and its integrity is essential to preserving a proper mitochondrial function. The second diseases group is led by defective nuclear and mitochondrial-encoded OXPHOS proteins. Some of these alterations include nuclear DNA deletions [126] and mutations in _POLG_, _MPV17_, _SUCLA2_, or _FBXLA_ genes [127; 128], which cause mitochondrial DNA depletion syndrome (MDS) or Alper's disease. Both mitochondrial and nuclear genome mutations can generate defects in the translation of mitochondrial proteins. Thus, mutations in _EARS2_, which encodes for mitochondrial aminoacyl-tRNA synthetase, cause mild-type leukoencephalopathy [129], and _MT-TL1_ and _MT-TK_ mutations generate MELAS [130] and MERRF [131] diseases, respectively. CoQ also participates as a cofactor in other enzymatic reactions upstream and downstream of the OXPHOS system. For example, as indicated above, CoQ receives electrons from many other dehydrogenases, such as electron-transferring flavoprotein dehydrogenase (ETFDH). Mutation in this gene causes multiple acyl-CoA dehydrogenation deficiency (MADD) characterized by a decrease in CoQ levels [132]. CoQ deficiency has been found in cardiofaciocutaneous syndrome where the _BRAF_ gene, encoding a serine/threonine-protein kinase, is mutated [133].