# Coenzyme Q at the Hinge of Health and Metabolic Diseases
## 4 CoQ Deficiency Syndrome
### Secondary CoQ Deficiency Due to Mitochondrial Dysfunction
Mutations in _ACADVL_, causing very long-chain Acyl-CoA dehydrogenase deficiency, and _TBC1D24_, which causes multifocal polymyoclonus and neurodevelopmental delay, have been associated with secondary CoQ deficiency [134; 135]. CoQ is distributed throughout the cell membranes after synthesis inside mitochondria, and extracellular CoQ can be imported into mitochondria [148; 15]. In yeast, the distribution of endogenously synthesized CoQ in mitochondria is affected by the _Ypl109c_ and _Ylr253w_ genes. _Ypl109c_ (_Cqd1_) is required to maintain CoQ in mitochondria. Its deletion increases CoQ exit from mitochondria, increasing the resistance to oxidative stress. _Ylr253w_ (_Cqd2_) promotes the opposite effects [149]. Interestingly, _Adck2_ (a mammal orthologose of _Ypl109c_) deletion causes mitochondrial deficiency in CoQ, leading to mitochondrial myopathy in skeletal muscle [150]. To reach mitochondria, exogenous CoQ requires a mechanism of import based on endocytosis and intracellular vesicular trafficking pathways, well conserved in all species. To date, six yeast transporter proteins (CDC10, RTS1, RVS161, RVS167, VPS1, and NAT3) represent the essential steps in the pathways responsible for the transport of exogenous CoQ to its functional sites in the cell [151]. Additionally, in yeast, the CoQ biosynthetic complex is organized in domains related to endoplasmic reticulum-mitochondria encounter structures called ER-mitochondria contact sites. Disorganization of these sites triggers secondary CoQ deficiency through a loss of mitochondrial membrane integrity compromising Q-synthome organization and the transfer of CoQ from and to mitochondria [21; 152]. CoQ-synthome and mitochondrial machinery organization could also be affected by a disruption of intracellular cholesterol trafficking towards mitochondria. In fact, an elevated mitochondrial cholesterol level has been detected in several mitochondrial pathological conditions, including Niemann-Pick Type C1-deficiency (NPC) [141], steatohepatitis [140], and Alzheimer's disease [139]. A study using in vitro and in vivo models of mitochondrial cholesterol enrichment displayed an impairment in oxidative phosphorylation and respiratory supercomplex assembly. This effect is due to the dysregulation of the enzyme in cholesterol synthesis 3-Hydroxy-3-Methylglutaryl-CoA reductase (HMG-CoAR), which may down-regulate the mevalonate pathway and CoQ synthesis [139]. Furthermore, mitochondrial cholesterol trafficking is controlled by proteins such as STAR and MLN64, among others. An overexpression of MLN64 [142] and mitochondrial aquaporin-8 (mtAQP8) [143] induce an increase in both mitochondrial cholesterol and dysfunction. In fact, it has been hypothesized that statin-induced CoQ deficiency inhibits HMG-CoAR, a common enzyme of CoQ and the cholesterol biosynthesis pathways [138]. The fifth group of causes of secondary CoQ deficiency is represented by a deficit in the activity of transporter proteins. The cholesterol could perturb other membrane carriers such as SLC25A11, which catalyzes the transport of 2-oxoglutarate to mitochondria. A cholesterol-mediated impairment of this carrier promotes mitochondrial GSH (mGSH) depletion, leading to increased oxidative stress [145]. Furthermore, mutations in the _ANO10_gene, which encodes for a carrier implicated in calcium signaling that is important for mitochondrial activity, has been associated with CoQ deficiency and ataxia [146]. Mutations in the _FXN_ gene encoding for frataxin, a protein that regulates the transport of iron into mitochondria, is related to ferprotosis, a regulated cell death associated with lipid peroxidation. Some patients with Friedrich ataxia harbored the _FXN_ mutation associated with low CoQ levels in skeletal muscle [122]. Recently, it has been observed that CoQ performs an important role in the DHODH-mediated defense mechanism against ferprotosis [153; 154]. Finally, mitochondrial homeostasis is the result of a balance between mitochondrial biogenesis and mitophagy.