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

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.

SUBMITTER: Douiev L

PROVIDER: S-EPMC7072316 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Douiev Liza L Sheffer Ruth R Horvath Gabriella G Saada Ann A

Cells 20200127 2

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 <i>DNM1L</i> gene result in a complex neurodevelopmental disorder with heterogeneous symptoms affecting multiple organ systems. Currently there is ...[more]

PMID: 32012656

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Project description:PRKAA (protein kinase, AMP-activated, α catalytic subunit) regulates mitochondrial biogenesis, function, and turnover. However, the molecular mechanisms by which PRKAA regulates mitochondrial dynamics remain poorly characterized. Here, we report that PRKAA regulated mitochondrial fission via the autophagy-dependent degradation of DNM1L (dynamin 1-like). Deletion of Prkaa1/AMPKα1 or Prkaa2/AMPKα2 resulted in defective autophagy, DNM1L accumulation, and aberrant mitochondrial fragmentation in the mouse aortic endothelium. Furthermore, autophagy inhibition by chloroquine treatment or ATG7 small interfering RNA (siRNA) transfection, upregulated DNM1L expression and triggered DNM1L-mediated mitochondrial fragmentation. In contrast, autophagy activation by overexpression of ATG7 or chronic administration of rapamycin, the MTOR inhibitor, promoted DNM1L degradation and attenuated mitochondrial fragmentation in Prkaa2-deficient (prkaa2-/-) mice, suggesting that defective autophagy contributes to enhanced DNM1L expression and mitochondrial fragmentation. Additionally, the autophagic receptor protein SQSTM1/p62, which bound to DNM1L and led to its translocation into the autophagosome, was involved in DNM1L degradation by the autophagy-lysosome pathway. Gene silencing of SQSTM1 markedly reduced the association between SQSTM1 and DNM1L, impaired the degradation of DNM1L, and enhanced mitochondrial fragmentation in PRKAA-deficient endothelial cells. Finally, the genetic (DNM1L siRNA) or pharmacological (mdivi-1) inhibition of DNMA1L ablated mitochondrial fragmentation in the mouse aortic endothelium and prevented the acetylcholine-induced relaxation of isolated mouse aortas. This suggests that aberrant DNM1L is responsible for enhanced mitochondrial fragmentation and endothelial dysfunction in prkaa knockout mice. Overall, our results show that PRKAA deletion promoted mitochondrial fragmentation in vascular endothelial cells by inhibiting the autophagy-dependent degradation of DNM1L.

Dataset Information

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

Publications

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

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