Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content

Abstract

Coenzyme Q 10 (CoQ 10 ) deficiency is associated to a variety of clinical phenotypes including neuromuscular and nephrotic disorders. We report two unrelated boys presenting encephalopathy, ataxia, and lactic acidosis, who died with necrotic lesions in different areas of brain. Levels of CoQ 10 and complex II+III activity were increased in both skeletal muscle and fibroblasts, but it was a consequence of higher mitochondria mass measured as citrate synthase. In fibroblasts, oxygen consumption was also increased, whereas steady state ATP levels were decreased. Antioxidant enzymes such as NQO1 and MnSOD and mitochondrial marker VDAC were overexpressed. Mitochondria recycling markers Fis1 and mitofusin, and mtDNA regulatory Tfam were reduced. Exome sequencing showed mutations in PDHA1 in the first patient and in PDHB in the second. These genes encode subunits of pyruvate dehydrogenase complex (PDH) that could explain the compensatory increase of CoQ 10 and a defect of mitochondrial homeostasis. These two cases describe, for the first time, a mitochondrial disease caused by PDH defects associated with unbalanced of both CoQ 10 content and mitochondria homeostasis, which severely affects the brain. Both CoQ 10 and mitochondria homeostasis appears as new markers for PDH associated mitochondrial disorders.

Proteomics Analysis Reveals Abnormal Electron Transport and Excessive Oxidative Stress Cause Mitochondrial Dysfunction in Placental Tissues of Early‐Onset Preeclampsia

“…PDHA located in the active site of PDH and assembled the inner structure of PDH complex . PDHA as a rate‐limiting step of the TCA cycle and the synthesis of ATP via the mitochondrial respiratory chain catalyzed the transformation process from oxidative decarboxylation of pyruvate to acetyl CoA . SUCLG1 as alpha subunit of the succinyl‐CoA targeted the mitochondria and then performed a reversible conversion of succinyl‐CoA and ADP or GDP to succinate and ATP or GTP .…”

Coenzyme Q10 Supplementation in Aging and Disease

“…For example, secondary CoQ 10 deficiency can appear in some patients with defects in glucose transport caused by GLUT1 mutations (Yubero et al, 2014 ). A group of patients with very severe neuropathies showed impaired CoQ 10 synthesis, indicating the importance of CoQ 10 homeostasis in human health (Asencio et al, 2016 ).…”

Role of the Pyruvate Dehydrogenase Complex in Metabolic Remodeling: Differential Pyruvate Dehydrogenase Complex Functions in Metabolism

“…Similarly, PDC deficiency in a fetus causes congenital lactic acidosis and malfunctioning of the central nervous system, which can be rescued by a ketogenic dietary formula composed of high fat, adequate protein, and low carbohydrate [ 53 ]. Several identified mutants in human PDC have been inherited in peripheral neuropathy and in severe encephalopathy, characterized by increased lactate production, decreased oxidative phosphorylation, and defective mitochondrial homeostasis [ 54 55 ]. A clinical study based on serum amino acid metabolite profiling demonstrates that metabolic dysfunction in myalgic encephalopathy/chronic fatigue syndrome is linked to defects in PDC activity, resulting in excessive lactate secretion, while the increased mitochondrial respiration utilizes the amino acids [ 56 ].…”