ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts

Abstract

Ethylmalonic encephalopathy protein 1 (ETHE1) and molybdenum cofactor (MoCo) deficiencies are hereditary disorders that affect the catabolism of sulfur-containing amino acids. ETHE1 deficiency is caused by mutations in the ETHE1 gene, while MoCo deficiency is due to mutations in one of three genes involved in MoCo biosynthesis ( MOCS1 , MOCS2 and GPHN ). Patients with both disorders exhibit abnormalities of the mitochondrial respiratory chain, among other biochemical findings. However, the pathophysiology of the defects has not been elucidated. To characterize cellular derangements, mitochondrial bioenergetics, dynamics, endoplasmic reticulum (ER)-mitochondria communication, superoxide production and apoptosis were evaluated in fibroblasts from four patients with ETHE1 deficiency and one with MOCS1 deficiency. The effect of JP4-039, a promising mitochondrial-targeted antioxidant, was also tested on cells. Our data show that mitochondrial respiration was decreased in all patient cell lines. ATP depletion and increased mitochondrial mass was identified in the same cells, while variable alterations in mitochondrial fusion and fission were seen. High superoxide levels were found in all cells and were decreased by treatment with JP4-039, while the respiratory chain activity was increased by this antioxidant in cells in which it was impaired. The content of VDAC1 and IP3R, proteins involved in ER-mitochondria communication, was decreased, while DDIT3, a marker of ER stress, and apoptosis were increased in all cell lines. These data demonstrate that previously unrecognized broad disturbances of cellular function are involved in the pathophysiology of ETHE1 and MOCS1 deficiencies, and that reduction of mitochondrial superoxide by JP4-039 is a promising strategy for adjuvant therapy of these disorders.

Sulfite Alters the Mitochondrial Network in Molybdenum Cofactor Deficiency

“…In a recent study, Grings et al (2019) reported that MOCS1 patient fibroblasts display altered protein levels of mitofusins 1 and 2, indicating a disturbance of mitochondrial dynamics. We analyzed the mitochondrial network in different cell culture models of SO deficiency and found that the mitochondria were hyperfused in the vast majority of SO-deficient cells.…”

“…Intriguingly, H 2 S has been reported to interfere with cellular respiration via inhibition of cytochrome c oxidase ( Tiranti et al, 2009 ). First attempts have recently been made to improve mitochondrial respiratory function in fibroblasts from ETHE1 and MOCS1 patients by treating cells with the mitochondria-targeted antioxidant JP4-039 ( Grings et al, 2019 ). While these results are promising, future studies should aim for further dissection of the underlying molecular mechanisms that primarily drive mitochondrial pathology in neuronal tissues of SO deficiency models in order to provide new therapy options.…”

“…In particular, exogenous SO 3 2– decreased intracellular ATP levels, impaired cellular respiration and inhibited the mitochondrial enzymes glutamate dehydrogenase and malate dehydrogenase. Recently, impairment of mitochondrial respiration has also been shown in various patient cell lines with defects in cysteine catabolism ( Grings et al, 2019 ).…”

The mitochondrial‐targeted reactive species scavenger JP4‐039 prevents sulfite‐induced alterations in antioxidant defenses, energy transfer, and cell death signaling in striatum of rats

“…19,20 Treatment with JP4-039 has also been demonstrated to decrease ROS in cells from patients with MoCo, ACAD9, and very long chain acyl-CoA dehydrogenase deficiencies, defects of mitochondrial oxidative phosphorylation and fatty acid oxidation, respectively. [21][22][23] In the present study, we evaluated the in vivo effect of intrastriatal administration of sulfite in rats on antioxidant defenses, creatine kinase (CK) activity, mitogenactivated protein kinases (MAPK) signaling pathways, and apoptosis markers. We also investigated the ability of JP4-039 to protect against the deleterious effects elicited by sulfite exposure.…”

Mitochondrial diseases: expanding the diagnosis in the era of genetic testing

“…Biallelic variants in ETHE1 demonstrate early onset progressive psychomotor retardation, cerebral hemorrhagic lesions, chronic diarrhea, and early death [360] . The exact mechanism of mitochondrial dysfunction remains unclear, but cell culture studies suggest impairments of ATP production, dynamics, and disruption of ER-mitochondria contacts [361] .…”