Mitochondrial energetics is impaired in very long-chain acyl-CoA dehydrogenase deficiency and can be rescued by treatment with mitochondria-targeted electron scavengers

Abstract

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common defect of mitochondrial long-chain fatty acid -oxidation. Patients present with heterogeneous clinical phenotypes affecting heart, liver and skeletal muscle predominantly. The full pathophysiology of the disease is unclear and patient response to current therapeutic regimens is incomplete. To identify additional cellular alterations and explore more effective therapies, mitochondrial bioenergetics and redox homeostasis were assessed in VLCAD-deficient fibroblasts, and several protective compounds were evaluated. The results revealed cellular and tissue changes, including decreased respiratory chain (RC) function, increased reactive oxygen species (ROS) production and altered mitochondrial function and signaling pathways in a variety of VLCAD-deficient fibroblasts. The mitochondrially enriched electron and free radical scavengers JP4-039 and XJB-5-131 improved RC function and decreased ROS production significantly, suggesting that they are viable candidate compounds to further develop to treat VLCAD-deficient patients.

Mitochondrial energetic impairment in a patient with late‐onset glutaric acidemia Type 2

“…Additional studies revealed increased reactive oxygen species (ROS), decreased spare respiratory capacity, increased basal oxygen consumption, and decreased steady-state cellular ATP level consistent with mitochondrial dysfunction and energy homeostasis impairment. Previous studies in cells of patients with ACAD9 related Complex I deficiency (Leipnitz et al, 2018) and VLCAD deficiency (Seminotti et al, 2019) found similar results. ATP synthesis is likely reduced due to respiratory chain supercomplex instability as well as reduced flux of reducing equivalents from ETFDH to ETC Complex III.…”

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

“…The affinity of the antibiotic Gramicidin S for the bacterial membrane has inspired the chemical structure of the JP4-039 molecule, a new, mitochondrial-targeted antioxidant drug [ 265 ]. JP4-039 displayed electron scavenger properties in animal models and in several tumor cell lines, as well as to improve mitochondrial respiration and scavenge ROS in ACAD9 - [ 266 ] and in Very Long-Chain Acyl-CoA Dehydrogenase ( VLCAD )- mutant fibroblasts [ 267 ]. Similar results have been reported in ETHE1 and MOCS1 mutant cell lines, in which JP4-039 treatment did increase the oxygen consumption rate, ATP production, and decrease superoxide levels.…”

Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner

“…Consequently, these expression patterns fit with the enhanced ROS levels and the uncoupling of mitochondria from other organelles such as the endoplasmic reticulum [ 24 ]. In connection with the impaired mitochondrial function of the USF2 lacking cells is also the reduction in Atp5j , and Acadvl expression which goes in line with a reduced mitochondrial ATP synthesis and beta-oxidation capacity [ 25 ], respectively.…”