Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease.

Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical presentations. Here, we report four individuals, including two siblings, affected by a progressive mitochondrial encephalopathy with biallelic variants in the cardiolipin biosynthesis gene CRLS1. Three affected individuals had a similar infantile presentation comprising progressive encephalopathy, bull's eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. The fourth affected individual presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. Using patient-derived fibroblasts, we characterized cardiolipin synthase 1 (CRLS1) dysfunction that impaired mitochondrial morphology and biogenesis, providing functional evidence that the CRLS1 variants cause mitochondrial disease. Lipid profiling in fibroblasts from two patients further confirmed the functional defect demonstrating reduced cardiolipin levels, altered acyl-chain composition and significantly increased levels of phosphatidylglycerol, the substrate of CRLS1. Proteomic profiling of patient cells and mouse Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. These findings support that deleterious variants in CRLS1 cause an autosomal recessive mitochondrial disease, presenting as a severe encephalopathy with multi-systemic involvement. Furthermore, we identify key signatures in cardiolipin and proteome profiles across various degrees of cardiolipin loss, facilitating the use of omics technologies to guide future diagnosis of mitochondrial diseases.

A baseline study of per- and polyfluoroalkyl substances (PFASs) in waterfowl from a remote Australian environment.

Elevated concentrations of PFASs in the liver may pose a toxicological risk to bird species and humans that consume them. This study aimed to determine concentrations of 43 per- and polyfluoroalkyl substances (PFASs) in livers (n = 80) of Australian Shelducks (Tadorna tadornoides), Pacific Black Ducks (Anas superciliosa), and Teals (Anas sp.), as well as water and sediment from a remote Australian environment. Maximum concentrations of PFBA (1.9 ng L-1), PFOA (1.7 ng L-1) and PFOS (0.99 ng L-1) in water were consistent with long-range atmospheric and oceanic transport. PFOS (30%) and PFNA (22%) were the most frequently detected PFASs in Australian Shelduck livers (0.31 ± 0.68 ng g-1 ww and 0.16 ± 0.15 ng g-1 ww respectively). Maximum concentrations of PFOS in Pacific Black Ducks (50%) and Teals (44%) was 2.4 ng g-1 ww and 5.3 ng g-1 ww respectively. While PFAS levels in birds from this remote environment were below current animal consumption guidelines, continued monitoring of this ecosystem is recommended to assess the human health risk of consumption of wild game.

Oxidative damage of proline residues by nitrate radicals (NO3˙): a kinetic and product study.

Tertiary amides, such as in N-acylated proline or N-methyl glycine residues, react rapidly with nitrate radicals (NO3˙) with absolute rate coefficients in the range of 4-7 × 108 M-1 s-1 in acetonitrile. The major pathway proceeds through oxidative electron transfer (ET) at nitrogen, whereas hydrogen abstraction is only a minor contributor under these conditions. However, steric hindrance at the amide, for example by alkyl side chains at the α-carbon, lowers the rate coefficient by up to 75%, indicating that NO3˙-induced oxidation of amide bonds proceeds through initial formation of a charge transfer complex. Furthermore, the rate of oxidative damage of proline and N-methyl glycine is significantly influenced by its position in a peptide. Thus, neighbouring peptide bonds, particularly in the N-direction, reduce the electron density at the tertiary amide, which slows down the rate of ET by up to one order of magnitude. The results from these model studies suggest that the susceptibility of proline residues in peptides to radical-induced oxidative damage should be considerably reduced, compared with the single amino acid.