Abstract
INTRODUCTION: Elucidating molecular alterations due to mitochondrial Complex I (CI) mutations may help to understand CI deficiency (CID), not only in mitochondriopathies but also as it is caused by drugs or associated to many diseases. OBJECTIVES: CID metabolic expression was investigated in Leber's hereditary optic neuropathy (LHON) caused by an inherited mutation of CI. METHODS: NMR-based metabolomics analysis was performed in intact skin fibroblasts from LHON patients. It used several datasets: one-dimensional (1)H-NMR spectra, two-dimensional (1)H-NMR spectra and quantified metabolites. Spectra were analysed using orthogonal partial least squares-discriminant analysis (OPLS-DA), and quantified metabolites using univariate statistics. The response to idebenone (IDE) and resveratrol (RSV), two agents improving CI activity and mitochondrial functions was evaluated. RESULTS: LHON fibroblasts had decreased CI activity (- 43%, p < 0.01). Metabolomics revealed prominent alterations in LHON including the increase of fatty acids (FA), polyunsaturated FA and phosphatidylcholine with a variable importance in the prediction (VIP) > 1 in OPLS-DA, p < 0.01 in univariate statistics, and the decrease of amino acids (AA), predominantly glycine, glutamate, glutamine (VIP > 1) and alanine (VIP > 1, p < 0.05). In LHON, treatment with IDE and RSV increased CI activity (+ 40 and + 44%, p < 0.05). IDE decreased FA, polyunsaturated FA and phosphatidylcholine (p < 0.05), but did not modified AA levels. RSV decreased polyunsaturated FA, and increased several AA (VIP > 1 and/or p < 0.05). CONCLUSION: LHON fibroblasts display lipid and amino acid metabolism alterations that are reversed by mitochondria-targeted treatments, and can be related to adaptive changes. Findings bring insights into molecular changes induced by CI mutation and, beyond, CID of other origins.