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

Abstract

A 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.

Figure 1. Principal-Component Analysis Discriminates LSFC Patients and Controls

For each panel, the post-quality control, imputed data set was used to perform the analysis. (A) Platform 1; PC1 and PC2 account for 18% and 13% of variation, respectively. (B) Platform 2; PC1 and PC2 account for 17% and 14% of variation, respectively. Loading scores are reported in Table S3; see also Figure S1 for an overview of analytes submitted to the PCA and Table S2 for raw data sets.

Figure 2. Individual Analytes with Statistical Significance in LSFC Patients versus Controls

(A) Platform 1; (B) Platform 2. Each dot represents a log2-transformed patient/matched control ratio. Metabolites are ordered by mean log2-transformed patient/control ratio. See also Figure S2 for data presented as volcano plots, Figure S1 for a summary of measured analytes, and Table S2 for log2-transformed ratios and p values of all analytes.

Figure 3. Quantitative Profiling of Metabolites Reflective of NADH/NAD⁺ Redox Status

Metabolites are shown in scatter dot plots with line indicating the mean. *p < 0.05 patients versus controls. See also Table S2 for raw data.

Figure 4. Pathway Relationship of Major Metabolic Alterations in LSFC Patients

This scheme depicts pathways related to reported perturbations in cytosolic and mitochondrial NADH accumulation, disrupted citric acid cycle (CAC), fatty acid β-oxidation, and amino acid metabolism, with a specific emphasis on those linked to α-hydroxybutyrate formation. Metabolites whose levels increased are indicated in red and with an upward arrow; those whose levels decreased are indicated in green and with a downward arrow. Metabolites whose levels did not change significantly are indicated in black with a sideways arrow. Those metabolites that were not measured are indicated in black (with no arrow). See also Figure S1 for an overview of analytes measured in the study and Table S2 for raw data and p values.