Identifying Rare Metabolic Disorders of Energy Dysfunction in Patients with Treatment-Resistant Depression


Presented By:

Kaitlyn Bloom, Ph.D.1, Michael Arcieri1, Yu Leng Phua, Ph.D.1, Lisa Pan, M.D.3,
Jerry Vockley, M.D., Ph.D 1,2,4.

1School of Medicine, University of Pittsburgh, Pittsburgh, 15224, USA; 2Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA; 3Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260; 4Center for Rare Disease Therapy, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224.

*Corresponding author. Department of Pediatrics, Children Hospital of Pittsburgh, Rangos Research Center 5157,
4401 Penn Avenue, Pittsburgh, PA 15224. Phone +1 (412) 692-7746. Fax: +1 (412) 692-7816. E-mail:

Background: Major depressive disorder (MDD) affects >350 million people worldwide, with 15% ultimately proving to have treatment-resistant depression (TRD). Through targeted metabolomics analysis, we have identified a variety of metabolite abnormalities in 55% of patients with TRD. Further investigation has revealed a subset with profiles consistent with a disruption of energy metabolism.

Methods: Functional studies performed on fibroblasts from 3 patients who had TRD and metabolite signals of energy dysfunction included acylcarnitine profile from cell culture medium, whole cell oxygen consumption using Seahorse XFe96 Extracellular Flux Analyzer, and whole cell fatty acid oxidation measured with 9,10-[3H]palmitate. Western blot, transcriptomics, and genome sequencing were also performed.

Results: TRD fibroblasts demonstrated decreased maximum respiration and spare respiratory capacity and flux through fatty acid oxidation pathway was decreased. Treatment with riboflavin improved fatty acid oxidation flux in one patient cell line, and respiratory chain function in another. The patient had a heterozygous variant in ETFB and demonstrated decreased expression of the ETFB gene. The second patient showed a homozygous variant in the DARS2 gene, which encodes a mitochondrial aminoacyltRNA synthetase. RNA sequencing analysis demonstrated significant downregulation in response to oxidative stress, reactive oxygen species, and ATP, and upregulation in response to cAMP catabolic processes and neurogenesis.

Discussion: TRD patient-derived fibroblasts rom patients with biochemical signatures of energy dysfunction exhibit primary and/or secondary disruptions of mitochondrial fatty acid oxidation, oxidative phosphorylation, or their interaction. Further characterization of energy pathways in these individuals may provide insight into treating their psychiatric symptoms and elucidate new theories for TRD pathogenesis.

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