New Metabolic Signature of Mitochondrial Dysfunction Revealed in Leigh Syndrome Variant

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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In a new study entitled “A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome,” a team of scientists performed a metabolomics analysis of plasma and urine samples from patients with Leigh syndrome and found a distinct metabolic signature of mitochondrial dysfunction. The study was published in the journal Cell Reports.

Mitochondrial dysfunction is increasingly recognized to be associated with common age-associated diseases and with the aging process itself, while metabolic diseases are caused by inherited mitochondria defects.

In this new study, researchers investigated the mitochondria metabolic profile of a cohort of patients with Leigh syndrome French Canadian variant (LSFC), a syndrome where patients exhibit several hallmarks of mitochondrial disorders, such as lactic acidosis (characterized by low pH in body tissues and blood accompanied by the buildup of lactate) and Leigh syndrome, a rare, severe, genetic neurological disorder that typically arises in the first year of life and leads to death within a couple of years due to respiratory failure, caused by a mutation in mitochondrial DNA in 20 to 25 percent of cases.

Researchers recruited LSFC patients and performed metabolic profiling using plasma and urine samples (collected in a prospective, case-control study) by targeted mass spectrometry (a technique that allows quantitation of proteins). They found that LSFC patients exhibit a distinct metabolic signature when compared to controls. This signature consists of 45 compounds that are associated with different metabolic pathways, such as cardiometabolic risk, disrupted NADH/NAD+, but also lipid and amino acid metabolism. Specifically, the results suggest that LSFC patients have an increased global cardiometabolic risk, despite the fact that they are relatively young (mean age of 22 years old). As expected, they showed disturbances in pathways linked to energy metabolism and mitochondria redox status (NADH/NAD+ ratio). Beyond mitochondrial energy metabolic pathways, researchers also observed that LSFC patients have perturbations in the metabolism of several amino acids.

The research team highlights that their findings support the power of using a metabolomics approach in Leigh syndrome, where they uncovered a LSFC metabolic signature that reflects alterations that may likely associate with mitochondrial dysfunction. Future studies should investigate the metabolic mechanisms underlying these alterations and potentially determine if the identified metabolites may be used as biological markers for disease severity, progression, and response to therapeutics in patients with LSFC.