A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome

Abstract

SUMMARYA decline in mitochondrial respiration represents the root cause of a large number of inborn errors of metabolism. It is also associated with common age-associated diseases and the aging process. To gain insight into the systemic, biochemical consequences of respiratory chain dysfunction, we performed a case-control, prospective metabolic profiling study in a genetically homogenous cohort of patients with Leigh syndrome French Canadian variant, a mitochondrial respiratory chain disease due to loss-of-function mutations in LRPPRC. We discovered 45 plasma and urinary analytes discriminating patients from controls, including classic markers of mitochondrial metabolic dysfunction (lactate and acylcarnitines), as well as unexpected markers of cardiometabolic risk (insulin and adiponectin), amino acid catabolism linked to NADH status (α-hydroxybutyrate), and NAD+ biosynthesis (kynurenine and 3-hydroxyanthranilic acid). Our study identifies systemic, metabolic pathway derangements that can lie downstream of primary mitochondrial lesions, with implications for understanding how the organelle contributes to rare and common diseases.

Metabolic effects of bezafibrate in mitochondrial disease

“…This raises the possibility that treatment led to an exacerbation of the mitochondrial pathology in patients with the m.3243A>G mutation, although given the lack of specificity of GDF-15 and FGF-21, it is also plausible that the changes we observed were due to the direct effects of bezafibrate on metabolism independent of oxidative phosphorylation. Following bezafibrate treatment, we also saw an alteration of metabolic pathways involving glutamine metabolism and the tricarboxylic acid (TCA) cycle (Buzkova et al, 2018), as well as an increase in the level of several amino acids including histidine, alanine, aspartate and N-acetyl-aspartate (NAA) (Thompson Legault et al, 2015). Glutamine is an abundant circulating amino acid and has an anaplerotic role, replenishing TCA cycle intermediates, which drive the mitochondrial respiratory chain to generate reducing equivalents (Mullen et al, 2014;Chen et al, 2018).…”

Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers

“…Sorbitol and myoinositol have not been reported previously to be changed in MDs. Elevated cystathionine was found in single patients with mtDNA depletion syndrome (Tadiboyina et al , ; Mudd et al , ), but not in blood samples of patients with Leigh syndrome (Thompson Legault et al , ), caused by a structural defect of the respiratory chain. Alanine is a standard blood biomarker in MDs (Haas et al , ), but is also found increased in other conditions, including sepsis, tetraspasticity, hyperinsulinism, chronic thiamine deficiency or as a side effect of valproic acid treatment (Thabet et al , ; Noguera et al , ; Thauvin‐Robinet et al , ; Morava et al , ).…”

Hypoxia as a therapy for mitochondrial disease

“…Recently, α-hydroxybutyrate (α-HB) was identified as a novel circulating plasma marker of Leigh syndrome (39). Consistent with this, we found that α-HB is elevated in the plasma of Ndufs4 KO mice breathing ambient air, but not in Ndufs4 KO mice treated with chronic hypoxia (Fig.…”