ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency

Abstract

Fatty acids and glucose are the main bioenergetic substrates in mammals that are alternatively used during the transition between fasting and feeding. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsufficiency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics-metabolomics). The data show that Aldh2+/- mice exhibits impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in CoQ biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation.

Micellization of coenzyme Q by the fungicide caspofungin allows for safe intravenous administration to reach extreme supraphysiological concentrations

“…S18 ). Previous studies with mice showed that oral CoQ 10 supplementation in wild-type animals can result in some uptake in the liver, ovaries and brown adipose tissue but perhaps not in other tissues despite sporadic positive reports [ 68 , 73 , 83 , [88] , [89] , [90] ]. In the present study, we directly compared oral feeding with LiQsorb at a ~1.6 times higher dose than that used with IV CF/CoQ 10 and observed only low plasma concentrations ( Fig.…”

UbiB proteins regulate cellular CoQ distribution

“…CoQ. Furthermore, a recent study reported that haploinsufficiency of human CQD1 ortholog ADCK2 led to aberrant mitochondrial lipid oxidation and myopathy associated with CoQ deficiency 14 .…”

A case report of adult-onset COQ8B nephropathy presenting focal segmental glomerulosclerosis with granular swollen podocytes

“…CoQ10 is a mitochondrial coenzyme that is essential for the mitochondrial respiratory chain and ATP production. A set of at least 17 different genes synthesized CoQ10 in mitochondria [13][14][15][16][17]. Of these, mutations in ten genes (prenyl diphosphate synthase subunit 1 [PDSS1], PDSS2, COQ2, COQ4, COQ6, COQ7, COQ8A, COQ8B, COQ9, and AarF domain containing kinase 2) cause primary CoQ10 deficiency [17,18].…”

“…A set of at least 17 different genes synthesized CoQ10 in mitochondria [13][14][15][16][17]. Of these, mutations in ten genes (prenyl diphosphate synthase subunit 1 [PDSS1], PDSS2, COQ2, COQ4, COQ6, COQ7, COQ8A, COQ8B, COQ9, and AarF domain containing kinase 2) cause primary CoQ10 deficiency [17,18]. Many signs and symptoms of CoQ10 deficient patients are common among other mitochondrial diseases; these involve multiple organ systems and often show prominent neurologic and myopathic features.…”