Abstract
Mitochondria are involved in many cellular processes and their main role is cellular energy production. They constantly undergo fission and fusion, and these counteracting processes are under strict balance. The cytosolic dynamin-related protein 1, Drp1, or dynamin-1-like protein (DNM1L) mediates mitochondrial and peroxisomal division. Defects in the DNM1L gene result in a complex neurodevelopmental disorder with heterogeneous symptoms affecting multiple organ systems. Currently there is no curative treatment available for this condition. We have previously described a patient with a de novo heterozygous c.1084G>A (p.G362S) DNM1L mutation and studied the effects of a small molecule, bezafibrate, on mitochondrial functions in this patient’s fibroblasts compared to controls. Bezafibrate normalized growth on glucose-free medium, as well as ATP production and oxygen consumption. It improved mitochondrial morphology in the patient’s fibroblasts, although causing a mild increase in ROS production at the same time. A human foreskin fibroblast cell line overexpressing the p.G362S mutation showed aberrant mitochondrial morphology, which normalized in the presence of bezafibrate. Further studies would be needed to show the consistency of the response to bezafibrate, possibly using fibroblasts from patients with different mutations in DNM1L, and this treatment should be confirmed in clinical trials. However, taking into account the favorable effects in our study, we suggest that bezafibrate could be offered as a treatment option for patients with certain DNM1L mutations.
Highlights
Mitochondria are cytosolic double-membrane-bound organelles found in nucleated eukaryotic cells
ATP production, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were evaluated as follows—cell content was measured by a colorimetric method using methylene blue (MB), which we have previously shown to reflect cell count [33,34]
Mitochondrial morphology was visualized using MitoTracker Red CM-H2XRos (MTR)/A total of 3 × 105 fibroblasts were seeded on 35 mm glass-bottom tissue culture plates in high-glucose medium and incubated with or without bezafibrate at 37 ◦ C, 5% CO2
Summary
Mitochondria are cytosolic double-membrane-bound organelles found in nucleated eukaryotic cells They are involved in many cellular processes, including the regulation of cell proliferation and differentiation, intracellular calcium homeostasis, regulation of cell death, among others. Mitochondria are highly dynamic organelles, constantly undergoing fission and fusion Their number, shape and location undergo changes throughout the cell cycle depending on different environmental conditions and energy status. The use of small molecules aims to improve mitochondrial function, such as respiratory efficiency, ATP production, and reduction of the free radicals, among others These small molecules are divided into several groups and include antioxidants, cofactors, mitochondrial biogenesis promoting factors, and others [28,29,30,31]. Our results suggest a possible therapeutic intervention for patients that carry mutations in this fission gene
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