Journal Article

Bezafibrate Improves Mitochondrial Fission and Function in DNM1L-Deficient Patient Cells

Horvath, Gabriella, Sheffer, Ruth, Douiev, Liza, Saada, Ann

2020

Overview

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.

• Publisher: MDPI,MDPI AG
• Subject: Adenosine Triphosphate - biosynthesis / bezafibrate / Bezafibrate - pharmacology / Cell Proliferation - drug effects / Cell Survival - drug effects / dnm1l / drp1 / Dynamins - deficiency / Dynamins - metabolism / fibroblast / Fibroblasts - drug effects / Fibroblasts - metabolism / Fibroblasts - pathology / Humans / Male / Membrane Potential, Mitochondrial - drug effects / mitochondrial disease / Mitochondrial Dynamics - drug effects / mitochondrial fission-fusion / Mutation - genetics / Oxygen Consumption - drug effects / Reactive Oxygen Species - metabolism