Abstract
IntroductionElucidating 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.ObjectivesCID metabolic expression was investigated in Leber’s hereditary optic neuropathy (LHON) caused by an inherited mutation of CI.MethodsNMR-based metabolomics analysis was performed in intact skin fibroblasts from LHON patients. It used several datasets: one-dimensional 1H-NMR spectra, two-dimensional 1H-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.ResultsLHON 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).ConclusionLHON 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.
Highlights
Elucidating molecular alterations due to mitochondrial Complex I (CI) mutations may help to understand CI deficiency (CID), in mitochondriopathies and as it is caused by drugs or associated to many diseases
Elucidating biochemical alterations in these diseases may help to understand CI deficiency (CID), in mitochondrial diseases, and as it is caused by drugs targeting CI, or is a pathogenic component of diseases including neurodegeneration and cancer (Mimaki et al 2012)
We investigated using metabolomics Leber’s hereditary optic neuropathy (LHON), a mitochondrial disease caused by an inherited mutation of a mitochondrial DNA-encoded subunit of CI
Summary
Elucidating molecular alterations due to mitochondrial Complex I (CI) mutations may help to understand CI deficiency (CID), in mitochondriopathies and as it is caused by drugs or associated to many diseases. Elucidating biochemical alterations in these diseases may help to understand CI deficiency (CID), in mitochondrial diseases, and as it is caused by drugs targeting CI, or is a pathogenic component of diseases including neurodegeneration and cancer (Mimaki et al 2012). To this aim, we investigated using metabolomics Leber’s hereditary optic neuropathy (LHON), a mitochondrial disease caused by an inherited mutation of a mitochondrial DNA-encoded subunit of CI. Cells with CID have been shown to develop mechanisms of adaptation, including increased mitogenesis that may yield incomplete penetrance of the disease in LHON and AMP-activated protein kinase (AMPK) activation that improves cellular bioenergetics (Distelmaier et al 2015)
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