Lipidomics unveils lipid dyshomeostasis and low circulating plasmalogens as biomarkers in a monogenic mitochondrial disorder

Ruiz M, Cuillerier A, Daneault C, Deschȇnes S, Frayne IR, Bouchard B, Forest A, Legault JT, The LSFC Consertium, Vaz FM, Rioux JD, Burelle Y, and Des Rosiers C. (2019) Lipidomics unveils lipid dyshomeostasis and low circulating plasmalogens as biomarkers in a monogenic mitochondrial disorder. The Journal of Clinical Investigation

Mitochondrial diseases are inherited with a prevalence of 1:5000 and are the result of mitochondrial dysfunction, manifesting in a wide range of diseases with high mortality rates often in childhood. The most common cause is a mutation in the mitochondrial genome or mitochondria-targeted proteins including the leucine-rich pentatricopeptide repeat–containing protein (LRPPRC). Within the French-Canadian population of northeastern Quebec mutations in LRPPRC have been found to result in Leigh Syndrome (LSFC; Leigh Syndrome French-Canadian variant), with a prevalence of 1:2000. This is a severe neurological disorder resulting in progressive loss of cognitive and motor function. Mitochondrial diseases predominantly affect oxidative phosphorylation (OXPHOS) machinery, the process that forms adenosine triphosphate (ATP), and is a large part of the pathology of these diseases. Ruiz et al suggest that further understanding of disruptions in nutrient metabolism, commonly seen in LSFC patients caused by lipid-handling abnormalities, is necessary for developing interventions and managing patient’s symptoms. As well as the mitochondria, the peroxisome is important for the metabolism of many classes of lipids, and dysfunction of both organelles have been noted to be involved in hepatic steatosis, also called fatty liver disease, therefore therapies that target the peroxisome could also prove to be beneficial for some pathologies of mitochondrial dysfunction. The aim of this study was to determine whether peroxisomal lipid metabolism has a role in lipid dyshomeostasis observed in LSFC, which is typically attributed to mitochondrial dysfunction. Using targeted liquid chromatography-mass spectrometry (LC-MS) the researchers analyzed plasmalogen levels and other lipids in the plasma of 8 LSFC patients and plasma and liver samples from the H-Lrpprc-/- mouse model.

Targeted LC-MS was used to determine plasmalogen levels in plasma of LSFC patients after fasting or consuming a smoothie containing: 5.7 g total carbohydrate, 0.7 g fiber, 4.0 g sugar, 1.6 g protein, 2.8 g total lipid, 0.2 g saturated fat, 1.6 g monounsaturated fat, 1.1 g polyunsaturated fat, 0.8 g n-6 fatty acids, 0.2 g n-3 fatty acids, 16 mg sodium, and 115 mg potassium for a total volume of 100 ml. When fasted and after the consuming the smoothie, 6 out of 21 plasmalogen species were found to be significantly decreased by 0.5-0.7-fold in LSFC patients compared to controls. In addition, other lipid species involved in peroxisomal metabolism were studied including fatty acid species with a very-long-chain (VLCFAs), bile acids conjugated with glycine (glycol-BA) or taurine (taurine-BA). To look at changes in fatty acid metabolism, 91 acylcarnitines were analyzed and 25% of them were found to be increased in the fasted and nutrient-intake samples, which indicates alterations in mitochondrial long-chain fatty acid β-oxidation. Distubrances in peroxisomal metabolism were evaluated by measuring the levels of odd-numbered carbon chain ACs and very-long-chain ACs (VLCACs). The former showed increased levels compared to the controls, however, no differences were seen in very-long-chain ACs, between the LSFC patients and the control group. The unconjugated BAs were not found to differ between the LSFC patients and the controls, however the conjugated BAs studied were reduced by ~50% in the LSFC samples. A H-Lrpprc-/- mouse model was used to test the plasma for plasmalogen levels, and it was found that, similar to the human LSFC patients, 5 plasmalogen species were significantly decreased compared to controls. Disturbed mitochondrial β-oxidation was also seen in the H-Lrpprc-/- mouse livers, as demonstrated by increased levels of 28 ACs including both VLCACs and odd-numbered carbon chain ACs. Finally, the ratio of conjugated to unconjugated BA species was reduced in the liver of these mice.

Ruiz et al have demonstrated using both human LSFC patients and a mouse model of the disease, that in addition to the mitochondria, it is likely that peroxisomes play a role in the lipid dyshomeostasis present in this disease. As the peroxisome is an important organelle for plasmalogen, VLCAC, and BA synthesis, seeing an alteration in their levels indicates a potential dysfunction of the peroxisome, which could be effective indicators of LSFC. Further work to link the mitochondrial and peroxisomal metabolism defects is needed to decipher the role of each in these types of diseases. As both organelles engage in crosstalk for regular homeostasis, it is probable that in both mitochondrial and peroxisomal disorders, the metabolism of both organelle play a role in the clinical manifestations of disease.

Kaeli KnudsenOctober 29, 2020