Very long-/ and long Chain-3-Hydroxy Acyl CoA Dehydrogenase Deficiency correlates with deregulation of the mitochondrial fusion/fission machinery

Judith Hagenbuchner¹, Sabine Scholl-Bürgi², Michael J. Ausserlechner²*, and Daniela Karall²*

¹Departments of Pediatrics II and ²Pediatrics I, Medical University Innsbruck, Innsbruck, Austria

Abstract

Background: Patients diagnosed with LCHADD or VLCADD present with hypertrophic cardiomyopathy or muscle weakness which is caused by the accumulation of fatty acid metabolites due to inactivating mutations in the mitochondrial trifunctional protein.

Cell lines: Fibroblasts from patients diagnosed with LCHADD (8 patients) or VLCADD
(1 patient) were compared with fibroblasts from healthy children used as controls
by live cell fluorescence microscopy, immunoblot analyses, and glucose determination.

Results: In live cell imaging, 9/9 patient fibroblast cultures showed alterations in their mitochondrial structures compared to healthy controls. Main fusion protein 2 (MFN2) was decreased in all patients compared to healthy controls, ranging from 82% to 30%.
The expression of DNM1L, the main fission regulator, was increased in 8/9 patients.
In addition, we observed reduced cell growth in two patients measured, but increased glucose consumption per cell.

Conclusion: By analyzing mitochondrial morphology, we uncovered that mutations within the HADHA or the ACADVL gene do not only affect fatty acid oxidation, but lead
to significant changes in the DNM1L/MFN2 ratio and mitochondrial morphology shifting the metabolism of LCHADD and VLCADD fibroblasts towards glycolysis. Our results provide novel insights into the metabolic deficiencies of LCHADD/VLCADD patients.