Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency

Abstract

Malonyl-CoA-acyl carrier protein transacylase (MCAT) is an enzyme involved in mitochondrial fatty acid synthesis (mtFAS) and catalyzes the transfer of the malonyl moiety of malonyl-CoA to the mitochondrial acyl carrier protein (ACP). Previously, we showed that loss-of-function of mtFAS genes, including Mcat, is associated with severe loss of electron transport chain (ETC) complexes in mouse immortalized skeletal myoblasts (Nowinski et al., 2020). Here, we report a proband presenting with hypotonia, failure to thrive, nystagmus, and abnormal brain MRI findings. Using whole exome sequencing, we identified biallelic variants in MCAT. Protein levels for NDUFB8 and COXII, subunits of complex I and IV respectively, were markedly reduced in lymphoblasts and fibroblasts, as well as SDHB for complex II in fibroblasts. ETC enzyme activities were decreased in parallel. Re-expression of wild-type MCAT rescued the phenotype in patient fibroblasts. This is the first report of a patient with MCAT pathogenic variants and combined oxidative phosphorylation deficiency.

Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism

“…Impaired oxidative metabolism and ETC deficiency were also observed in MECR-deficient T cells. Reduced mitochondrial respiration, as seen by the mitochondrial stress test, agrees with other studies (Nowinski et al, 2020;Webb et al, 2023) in addition to reduced lipoic acid and ETC complexes I, II, and IV that LYRM proteins help stabilize. However, depending on mutations in the pathway, lipoic acid synthesis may be retained, as shown by a case study with a patient harboring a mutation in MCAT (Webb et al, 2023), confirming that lipoic acid is not the only biologically important product generated by the mtFAS pathway and supplementing lipoic acid does not rescue mitochondrial ETC assembly defects.…”

RecessiveMECRpathogenic variants cause an LHON-like optic neuropathy

“… 26 Moreover, pathogenic variants in both genes have been associated with a severe childhood-onset oxidative phosphorylation defect, also characterised by reduced levels of intact complexes/supercomplexes in the MCAT described case. 27 Conversely, we failed to observe such a drastic downstream consequence of mutant MECR on OXPHOS complexes and respiratory function in our patient-derived primary cultures of fibroblasts. As mentioned, the residual activity of MECR in these two patients may be sufficient to maintain a basal mitochondrial respiration, which might well be defective in neurons like the retinal ganglion cells.…”

Mitochondrial Phosphopantetheinylation is Required for Oxidative Function

“…We recently described a pathogenic variant in the mtFAS gene MCAT c.812T>C; p.T271I (rs760294168; NM_173467.4), which displayed perturbed ETC complex assembly and cellular respiration 23 . As our data demonstrate that perturbed Aasdhppt expression results in similar phenotypes in cultured mouse skeletal myoblasts, we wondered whether there may be patients with pathological variants in AASDHPPT .…”

“…Importantly, we evaluated the functionality of each variant in this study by testing their ability to rescue mtFAS impairment in PPT-deficient cells. As described above, to do so we ectopically expressed the missense mutation construct under the control of the constitutively expressed EF-1⍺ promoter, a strategy that we have successfully employed in the past to identify a functionally impaired variant of the mtFAS gene MCAT 23 . However, because this strategy relies on overexpression, it is possible that variants that cause weak impairments would be able to rescue fully in this assay, because of the high levels of expression.…”