Different mitochondrial genetic defects exhibit the same protein signature of metabolism in skeletal muscle of PEO and MELAS patients: A role for oxidative stress

Free Radic Biol Med. 2018 Oct;126:235-248. doi: 10.1016/j.freeradbiomed.2018.08.020. Epub 2018 Aug 20.


A major challenge in mitochondrial diseases (MDs) is the identification of biomarkers that could inform of the mechanisms involved in the phenotypic expression of genetic defects. Herein, we have investigated the protein signature of metabolism and of the antioxidant response in muscle biopsies of clinically and genetically diagnosed patients with Progressive External Ophthalmoplegia due to single large-scale (PEO-sD) or multiple (PEO-mD) deletions of mtDNA and Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like episode (MELAS) syndrome, and healthy donors. A high-throughput immunoassay technique that quantitates the expression of relevant proteins of glycolysis, glycogenolysis, pentose phosphate pathway, oxidative phosphorylation, pyruvate and fatty acid oxidation, tricarboxylic acid cycle and the antioxidant response in two large independent and retrospectively collected cohorts of PEO-sD, PEO-mD and MELAS patients revealed that despite the heterogeneity of the genetic alterations, the three MDs showed the same metabolic signatures in both cohorts of patients, which were highly divergent from those of healthy individuals. Linear Discriminant Analysis and Support Vector Machine classifier provided a minimum of four biomarkers to discriminate healthy from pathological samples. Regardless of the induction of a large number of enzymes involved in ameliorating oxidative stress, the down-regulation of mitochondrial superoxide dismutase (SOD2) and catalase expression favored the accumulation of oxidative damage in patients' proteins. Down-regulation of SOD2 and catalase expression in MD patients is not due to relevant changes in the availability of their mRNAs, suggesting that oxidative stress regulates the expression of the two enzymes post-transcriptionally. We suggest that SOD2 and catalase could provide specific targets to improve the detoxification of reactive oxygen species that affects muscle proteins in these patients.

Keywords: Catalase; Metabolic enzymes; Mitochondrial diseases; Mn-superoxide dismutase; Oxidative stress; Protein arrays.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antioxidants / metabolism
  • Biomarkers / metabolism
  • Biopsy
  • Child
  • Child, Preschool
  • DNA, Mitochondrial / genetics*
  • Gene Expression Regulation
  • Glycolysis
  • Healthy Volunteers
  • Humans
  • MELAS Syndrome / genetics
  • MELAS Syndrome / metabolism*
  • MELAS Syndrome / pathology
  • Middle Aged
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Ophthalmoplegia, Chronic Progressive External / genetics
  • Ophthalmoplegia, Chronic Progressive External / metabolism*
  • Ophthalmoplegia, Chronic Progressive External / pathology
  • Oxidative Stress
  • Reactive Oxygen Species
  • Superoxide Dismutase / genetics
  • Support Vector Machine
  • Young Adult


  • Antioxidants
  • Biomarkers
  • DNA, Mitochondrial
  • Reactive Oxygen Species
  • Superoxide Dismutase
  • superoxide dismutase 2