Lipid Peroxidation

Lipid peroxidation is the membrane-and-lipoprotein arm of oxidative stress. Antonio Ayala, Mario Munoz and Sandro Arguelles set the scale of the problem: a cell produces around 50 hydroxyl radicals every second, roughly 4 million in a day [1]. When those radicals hit polyunsaturated fatty acids, the chain reaction ends in two reactive aldehydes, malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE), both of which outlive the radical that made them and travel to modify distant targets [1].

4-HNE reacts with amino acid side chains in the order Cys much greater than His greater than Lys [1]. Its downstream effects are dose-dependent and not uniformly damaging. In NT2 neurons, low 4-HNE concentrations induced a 2 to 6 fold increase in intracellular amyloid beta production [1]. In human osteoarthritic osteoblasts, 4-HNE produced roughly a 70% decrease in TNF-alpha-induced IL-6 mRNA expression, an anti-inflammatory effect [1]. Phagocytosis of 4-HNE- and MDA-modified photoreceptor outer segments cut autophagy by 40% [1].

Giuseppina Barrera and colleagues place the source at the mitochondria, which generate roughly 1-5% of consumed oxygen as reactive species through electron leak, mostly at complexes I and III [2][4]. In myelodysplastic syndrome patients, MDA was significantly raised in those with iron overload against those without and against controls, and plasma MDA correlated positively with ferritin [2]. Iron is the catalyst that keeps the chain running.

The cardiovascular endpoint is oxidised LDL. A pooled analysis of case-control comparisons gives an oxLDL effect size of 0.44 (95% CI 0.11-0.77) between cases and controls, with individual studies ranging from 0.34 (0.20-0.48) to 0.75 (0.46-1.03) [3]. In one cohort, oxLDL carried a hazard ratio of 1.03 (95% CI 1.00-1.06, P = 0.035) per unit [3]. Whole-body damage rises with age: Courtney Peterson, Darcy Johannsen and Eric Ravussin report urinary isoprostanes 38% higher in adults aged 70 to 84 than in adults aged 20 to 34 [4].

What lowers it: coenzyme Q10. Zohreh Sadat Sangsefidi and colleagues pooled 19 randomised trials and found CoQ10 reduced MDA with a standardised mean difference of -1.12 (95% CI -1.58 to -0.65, p < .0001), while raising total antioxidant capacity (SMD 1.29, 95% CI 0.35-2.23, p = .007) and glutathione peroxidase (SMD 0.45, 95% CI 0.17-0.74, p = .002) [5]. Lowering a marker is not the same as lowering events; no trial has shown MDA reduction translates to fewer heart attacks.