Impaired lipid homeostasis and elevated lipid oxidation of erythrocyte membrane in adolescent depression

Abstract

Adolescent depression is a globally concerned mental health issue, the pathophysiological mechanisms of which remain elusive. Membrane lipids play a crucial role in brain development and function, potentially serving as a crossroad for the abnormalities in neurotransmitters, neuroendocrine, inflammation, oxidative stress, and energy metabolism observed in depressed adolescents. The primary aim of this study was to investigate the erythrocyte membrane lipid profile in adolescent depression. A total of 2838 erythrocyte membrane lipids were detected and quantified in 81 adolescents with depression and 67 matched healthy adolescents using ultra-high performance liquid chromatography-mass spectrometry. Depressed adolescents exhibited significantly different membrane lipid characteristics compared to healthy controls. Specifically, the levels of cholesterol, sphingomyelins, and ceramides were increased, while ether lipids were decreased in patients. Moreover, the patients showed reduced polyunsaturated fatty acids and elevated lipophilic index in membrane, suggesting diminished membrane fluidity. The higher oxidized membrane lipids and plasma malondialdehyde were observed in adolescent depression, indicating the presence of oxidative stress. Importantly, membrane lipid damage was associated with more severe depressive symptoms and worse cognitive function in patients. In addition, reduced polyunsaturated fatty acids and membrane fluidity may be partly responsible for the blunted niacin skin flushing response found in depressed adolescents. In conclusion, our results reveal impaired erythrocyte membrane lipid homeostasis in adolescents with depression, which may implicate membrane dysfunction in the brain. These findings offer new insights into the underlying molecular mechanisms of adolescent depression, highlighting the potential of counteracting membrane damage as a promising avenue for future therapeutic interventions.

Keywords: Adolescent depression; Cognitive function; Lipidome; Membrane fluidity; Niacin skin flushing response; Oxidative stress.

Graphical abstract

Fig. 1

Membrane lipid characteristics were significantly different between depressed adolescents and controls. (A) Quantity and abundance distribution of different lipid classes in the erythrocyte membrane. (B) OPLS-DA model and permutation testing of erythrocyte membrane lipidome. (C) The differences in 2838 lipids between depressed adolescents and controls, in which the marked p-value was obtained by hypergeometric test. p<0.05 indicates that the lipid class is significantly increased (right) or decreased (left) in adolescent depression. (D) Diagnostic efficacy of the combinational biomarker panel of 8 lipids. DD, Depressive Disorder; HC, Healthy Control; OPLS-DA, Orthogonal Partial Least Squares-Discriminant Analysis; GP, Glycerophospholipid; ST, Sterol Lipids; GL, Glycerolipid; SP, Sphingolipid; LPL, Lysophospholipid; PA, Phosphatidic Acid; PC, Phosphatidylcholine; PE, Phosphatidylethanolamine; PG, Phosphatidylglycerol; PI, Phosphatidylinositol; PS, Phosphatidylserine; CHO, Cholesterol; ChE, Cholesterol Ester; DG, Diglyceride; TG, Triglyceride; Cer, Ceramide; HexCer, Hexosyl Ceramide; SM, Sphingomyelin; LSM, Lysosphingomyelin; Ether.L, Ether Lipid; Oxid.L, Oxidized Lipid; FC, Fold Change; FDR, False Discovery Rate; AUC, Area Under the Curve.

Fig. 2

PUFA and membrane fluidity were decreased in adolescent depression. The difference of (A) fatty acids levels in different lipid classes, (B) n6/n3 PUFA ratio, (C) ratios of lysophospholipid to phospholipid, (D) chain length index, (E) unsaturation index, (F) lipophilic index, (G) cholesterol levels, and (H) PC/SM ratio between depressed adolescents and controls. ∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001, ∗∗∗∗p<0.0001. DD, Depressive Disorder; HC, Healthy Control; LPL, Lysophospholipid; PL, Phospholipid; LPA, Lysophosphatidic Acid; PA, Phosphatidic Acid; LPC, Lysophosphatidylcholine; PC, Phosphatidylcholine; LPE, Lysophosphatidylethanolamine; PE, Phosphatidylethanolamine; PG, Phosphatidylglycerol; LPI, Lysophosphatidylinositol; PI, Phosphatidylinositol; LPS, Lysophosphatidylserine; PS, Phosphatidylserine; Ether.L, Ether Lipid; ChE, Cholesterol Ester; DG, Diglyceride; TG, Triglyceride; Cer, Ceramide; HexCer, Hexosyl Ceramide; SM, Sphingomyelin; GP, Glycerophospholipid; ST, Sterol Lipids; GL, Glycerolipid; SP, Sphingolipid; SFA, Saturated Fatty Acids; MUFA, Monounsaturated Fatty Acids; PUFA, Polyunsaturated Fatty Acids; FC, Fold Change; FDR, False Discovery Rate.

Fig. 3

Lipid oxidation was increased in adolescent depression. The differences of (A) 324 oxidized lipids levels, (B) oxidized fatty acids levels (the inner diagram is the sum of different oxidized fatty acids), (C) peroxidation index, and (D) plasma MDA levels between depressed adolescents and controls. ∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001, ∗∗∗∗p<0.0001. DD, Depressive Disorder; HC, Healthy Control; LPL, Lysophospholipid; PA, Phosphatidic Acid; PC, Phosphatidylcholine; PE, Phosphatidylethanolamine; PI, Phosphatidylinositol; PS, Phosphatidylserine; TG, Triglyceride; Cer, Ceramide; HexCer, Hexosyl Ceramide; SFA, Saturated Fatty Acids; MUFA, Monounsaturated Fatty Acids; PUFA, Polyunsaturated Fatty Acids; MDA, Malondialdehyde; FC, Fold Change; FDR, False Discovery Rate.

Fig. 4

Membrane lipid homeostasis was associated with depressive symptom and cognitive function of adolescents with depression. (A) 8 lipid modules significantly associated with clinical symptoms. ∗p < 0.05. The composition of (B) lipid classes and (C) fatty acid chains in protection and risk modules. (D) The association between MoCA and WMS scores with n6/n3 PUFA ratio, lipophilic index, PC/SM ratio, peroxidation index, and total content of oxidized lipids. HAMD, Hamilton Depression Scale; MoCA, Montreal Cognitive Assessment; WMS, Wechsler Memory Scale; LPL, Lysophospholipid; PA, Phosphatidic Acid; PC, Phosphatidylcholine; PE, Phosphatidylethanolamine; PS, Phosphatidylserine; Cer, Ceramide; HexCer, Hexosyl Ceramide; SM, Sphingomyelin; Ether.L, Ether Lipid; Oxid.L, Oxidized Lipids; SFA, Saturated Fatty Acids; PUFA, Polyunsaturated Fatty Acids.

Fig. 5

Membrane lipid homeostasis was associated with niacin skin flushing response of adolescents with depression. (A) Weakened NSFR in adolescent depression. (B) Correlation between lipid modules and NSFR. ∗p < 0.05. (C) The composition of lipids classes and fatty acids chains in the greenyellow module. The association between NSFR with (D) unsaturation index, (E) lipophilic index, and (F) cholesterol levels. DD, Depressive Disorder; HC, Healthy Control; NSFR, Niacin Skin Flushing Response; PC, Phosphatidylcholine; PE, Phosphatidylethanolamine; PG, Phosphatidylglycerol; Ether.L, Ether Lipid; FA, Fatty Acids; SFA, Saturated Fatty Acids; MUFA, Monounsaturated Fatty Acids; PUFA, Polyunsaturated Fatty Acids.

Fig. 6

The disturbance of cell membrane lipid homeostasis was evident in adolescents suffering from depression. In comparison to healthy controls, depressed adolescents exhibited notable variations in membrane lipid composition, including elevated cholesterol, sphingomyelins, ceramides, and lipid oxidation, as well as reduced ether lipids, polyunsaturated fatty acids, and membrane fluidity. Moreover, membrane lipid damage was found to be associated with depressive symptoms, cognitive function, and niacin skin flushing response in adolescents with depression. These findings suggest that disruptions in membrane lipid composition may have systemic implications and contribute to aberrant neurotransmitter signaling at synapses, thereby playing a role in the onset and progression of adolescent depression. MDA, Malondialdehyde.