# Comprehensive metabolomic/lipidomic characterization of patients with mitochondrial ATP synthase, short-chain acyl-CoA dehydrogenase and combined variant deficiencies

## TL;DR

This study identifies unique metabolic patterns in patients with mitochondrial enzyme deficiencies, highlighting changes in energy metabolism, amino acid breakdown, and lipid levels.

## Contribution

The study provides a comprehensive metabolomic and lipidomic characterization of TMEM70d, SCADd, and combined deficiencies, revealing synergistic effects when both mutations are present.

## Key findings

- Patients with TMEM70d and SCADd show distinct metabolic profiles in urine and serum, including elevated butyrylcarnitine and branched-chain amino acid metabolites.
- Lipidomic analysis shows decreased glycerophospholipids and sphingolipids in all patient groups.
- The combination of TMEM70d and SCADd leads to synergistic metabolic effects, emphasizing the need for comprehensive profiling in mitochondrial disorders.

## Abstract

This study aims to characterize the metabolic alterations in patients with inherited mitochondrial enzymopathies. We focused on wide-coverage targeted metabolomic, organic acid and lipidomic analyses of patients with TMEM70 deficiency (TMEM70d), short-chain acyl-CoA dehydrogenase deficiency (SCADd), and individuals with both deficiencies (TMEM70d-SCADd).

Serum and urine samples were collected from patients with TMEM70d (n = 13), SCADd (n = 11), TMEM70d-SCADd (n = 3), and controls (n = 38). Analyses were conducted using high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Univariate and multivariate statistical evaluation was performed to identify significant metabolic differences between patient groups and controls.

Distinct metabolic profiles were observed in urine and serum samples of patients with TMEM70d, SCADd, and TMEM70d-SCADd compared to controls. Urinary metabolomics revealed significant elevations in butyrylcarnitine and metabolites related to branched-chain amino acid degradation in SCADd and TMEM70d-SCADd patients. Serum metabolomic analysis indicated alterations in pyruvate metabolism, citric acid cycle intermediates, and acylcarnitine metabolism in TMEM70d and TMEM70d-SCADd patients. Lipidomic analysis showed decreased levels of glycerophospholipids and sphingolipids across all patient groups.

Patients with TMEM70d, SCADd, and TMEM70d-SCADd exhibit distinct metabolic signatures characterized by disturbances in energy metabolism, amino acid degradation, and lipid homeostasis. The combination of TMEM70d and SCADd leads to synergistic metabolic effects, emphasizing the importance of comprehensive metabolic profiling in understanding complex mitochondrial disorders and identifying potential biomarkers for diagnosis and treatment monitoring.

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•Metabolomic and lipidomic analyses serve as an important tool to assess pathobiochemical changes in mitochondrial enzymopathies.•Distinct imbalances in the citric acid cycle, degradation of branched-chain amino acids and acylcarnitine metabolism were revealed in patients with mitochondrial disorders.•Marked lipid dysregulation in glycerophospholipids and sphingolipids levels was observed in all studied patients•The combination of TMEM70d and SCADd leads to a synergistic metabolic effect in patients with these mutations.

Metabolomic and lipidomic analyses serve as an important tool to assess pathobiochemical changes in mitochondrial enzymopathies.

Distinct imbalances in the citric acid cycle, degradation of branched-chain amino acids and acylcarnitine metabolism were revealed in patients with mitochondrial disorders.

Marked lipid dysregulation in glycerophospholipids and sphingolipids levels was observed in all studied patients

The combination of TMEM70d and SCADd leads to a synergistic metabolic effect in patients with these mutations.